Bifunctional compounds

ABSTRACT

The present application provides compounds that modulate CDK protein function. Methods of making the compounds, compositions containing the compounds, and uses of the compounds for treating or ameliorating of diseases, disorders, or conditions associated with CDK proteins, are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/522,481, filed Jul. 25, 2019; which claims the benefit of U.S.Provisional Application No. 62/711,164, filed Jul. 27, 2018; thedisclosure of each of which is incorporated herein by reference in itsentirety.

BACKGROUND Field

Compounds, methods of making such compounds, pharmaceutical compositionsand medicaments comprising such compounds, and methods of using suchcompounds to treat or diagnose diseases, disorders, or conditionsassociated with protein malfunctions are provided.

Description of the Related Technology

Protein kinases are critical components of the cell-signaling machinery.Kinases mediate cell-signaling by transferring a phosphoryl group from anucleoside triphosphate (NTP) to a protein acceptor. Thesephosphorylation events function as molecular on/off switches that canregulate the biological function of the target protein. Phosphorylationcan be triggered by a wide variety of extracellular and other stimuli,such as environmental and chemical stress signals, cytokines, and growthfactors. Thus, kinases facilitate cellular responses to such stimuli,in, for example, cell growth, migration, differentiation, secretion ofhormones, activation of transcription factors, metabolism, control ofprotein synthesis, and regulation of the cell cycle.

The initiation, progression through, and completion of the cell cycleare tightly regulated by various cyclin-dependent kinases (CDKs), whichare critical for normal cell growth. CDKs act as a complex with a CDKsubunit (the catalytic subunit) and a regulatory subunit (the cyclin).There are over ten known CDKs, many of which are involved in regulatingcell cycle progression, as well as having other functions. Accordingly,modulating CDK activity may provide advantageous anti-proliferativeactivity. Indeed, inhibitors of CDK4/6 such a palbociclib and ribociclibare currently on the market for the treatment of breast cancer.

Aberrant protein function, and/or protein imbalance is a hallmark ofmany disease states. For example, the functioning of the immune systemis finely balanced by the activities of pro-inflammatory andanti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, IL-4, IL-10, and IL-13 arepotent activators of B lymphocytes, and also act as anti-inflammatoryagents. They are anti-inflammatory cytokines by virtue of their abilityto suppress genes for pro-inflammatory cytokines such as IL-1, TNF, andchemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes, macrophages) become sensitizedagainst the “self.” Lymphocytes, as well as macrophages, are usuallyunder control in this system. However, a misdirection of the systemtoward the body's own tissues may happen in response to stillunexplained triggers. One hypothesis is that lymphocytes recognize anantigen which mimics the “self” and a cascade of activation of differentcomponents of the immune system takes place, ultimately leading totissue destruction. Genetic predisposition has also been postulated tobe responsible for autoimmune disorders.

Tumor necrosis factor-alpha (TNF-alpha, or TNF-α) and interleukin-1(IL-1) are pro-inflammatory cytokines that mediate inflammatoryresponses associated with infectious agents and other cellular stresses.Overproduction of these cytokines is believed to underlie theprogression of many inflammatory diseases including rheumatoid arthritis(RA), Crohn's disease, inflammatory bowel disease, endotoxin shock,osteoporosis, neurodegenerative diseases (such as multiple sclerosis,Alzheimer's disease, Parkinson's disease), congestive heart failure, andpsoriasis among others.

Recent data from clinical trials support the use of protein antagonistsof cytokines, for example soluble TNF-α receptor fusion protein(etanercept) or the monoclonal TNF-α antibody (infliximab), for thetreatment of rheumatoid arthritis, Crohn's disease, juvenile chronicarthritis and psoriatic arthritis. Thus, the reduction ofpro-inflammatory cytokines such as TNF-α and interleukin-1 (IL-I) hasbecome an accepted therapeutic approach for potential drug interventionin these conditions.

Moreover, IL-2 is now FDA approved for the treatment of renal cancer andmelanoma patients, with durable, complete remissions achieved with IL-2up to 148 months. However, the short half-life of IL-2 in serum requiresthat large amounts of IL-2 be injected to achieve therapeutic levels.Many attempts have been made to minimize side effects of systemic IL-2treatment, for example, introducing IL-2 directly into the tumor, thoughthis complicates treatment, and has largely been unsuccessful.

Local delivery of cytokines is appealing compared to systemic deliveryfor a variety of reasons. It takes advantage of the natural biology ofcytokines that have evolved to act locally in a paracrine or autocrinefashion. Local expression also dramatically minimizes many of the sideeffects of systemic delivery of cytokines. Thus, compounds and methodsto increase local expression of IL-2 would be better tolerated than highdose IL-2 treatment, which would expand therapeutic utility ofstrategies that increase IL-2.

Additional targets include several candidate genes involved in apoptosisand cell survival, including the translation termination factor GSPT1(eRF3a), casein kinase 1α (CK1α), and the zinc-finger transcriptionfactors aiolos, helios, and ikaros. Aiolos, helios, and ikaros aretranscription factors whose expression is restricted to lymphoidlineages. For example, aiolos binds to the Bcl-2 promoter, and alsointeracts with the Bcl-2 and Bcl-XL proteins to promote cell survival.Upregulation of aiolos expression, for example, can reduce apoptosis ofHIV-1 infected cells.

Likewise, expression of aiolos in lung and breast cancers predictssignificantly reduced patient survival. Aiolos decreases expression of alarge set of adhesion-related genes, disrupting cell-cell andcell-matrix interactions, facilitating metastasis. Aiolos may alsofunction as an epigenetic driver of lymphocyte mimicry in certainmetastatic epithelial cancers. Similarly, aberrant ikaros and heliosexpression may promote Bcl-XL expression, driving the development ofhematopoietic malignancies. Thus, down-regulation of aiolos, ikaros,and/or helios may reduce or eliminate metastasis.

GSPT1 mediates stop codon recognition and facilitates release of anascent peptide from the ribosome and is also involved in several othercritical cellular processes, such as cell cycle regulation, cytoskeletonorganization and apoptosis. Accordingly, decreased levels of GSPT1 mayimpair control of cell proliferation and facilitate cell migration andscar formation. Indeed, GSPT1 has been implicated as an oncogenic driverof several different cancer types, including breast cancer,hepatocellular carcinoma, gastric cancer, and prostate cancer. See,e.g., Brito, et al., Carcinogenesis, Vol. 26, No. 12, pp. 2046-49(2005); Brito, et al., Canc. Geneti. Cytogen., Vol. 195, pp. 132-42(2009); Tavassoli, et al., Med. Oncol., Vol. 29, pp. 1581-85 (2011);Wright and Lange, Rev. Urol., Vol. 9, No. 4, pp. 207-213 (2007);Hoshino, et al., Apoptosis, Vol. 17, pp. 1287-99 (2012); Liu, et. al.,PLOS One, Vol. 9, No. 1, e86371 (2014); and Jean-Jean, et al., Mol.Cell. Bio., Vol. 27, No. 16, pp. 5619-29 (2007). GSPT1 also contributesto glial scar formation and astrogliosis after a central nervous system(CNS) injury. See, e.g., Ishii et al., J. Biol. Chem., Vol. 292, No. 4,pp. 1240-50 (2017).

Casein kinase 1α (CK1α) is a component of the β-catenin-degradationcomplex and a critical regulator of the Wnt signaling pathway, and itsablation induces both Wnt and p53 activation. Schittek and Sinnberg,Mol. Cancer. 2014, 13, 231; Cheong and Virshup, J. Biochem. Cell Biol.2011, 43, 465-469; Elyada et al., Nature 2011, 470, 409-413. CK1αphosphorylates β-catenin, which is subsequently further phosphorylatedby GSK-30. This destabilizes β-catenin and marks the protein forubiquitination and proteasomal degradation. Thus, CK1α functions as amolecular switch for the Wnt pathway. Amit et al., Genes Dev. 2002, 16,1066-1076. CK1α is critical for embryogenesis and plays an importantrole in tissue development and response to DNA damage, at least partlycoordinated with p53. Elyada et al., Nature 2011, 470, 409-413;Schneider et al., Cancer Cell 2014, 26, 509-520. Levine and Oren, Nat.Rev. Cancer 2009, 9, 749-758.

Indeed, CK1α also phosphorylates p53, which inhibits binding to MDM2 (ap53 inhibitor) and stabilizes p53's binding interactions with thetranscriptional machinery. Huart, et al., J. Biol. Chem. 2009, 284,32384-32394. Thus, inhibiting CK1α activity increases cellular levels ofp53. This is of particular importance for skin cancer, which has killedmore people since 1980 than all other types of cancer combined. Stern,Arch Dermatol. 2010, 146, 279-282.

Most kinase inhibitors function by blocking the NTP binding site on thekinase. However, given the structural similarity of endogenous NTPs,kinase inhibitors may produce undesirable off-target effects byunintended, non-specific interactions, or via pathway cross-talk. Onemechanism to disrupt protein drivers of disease is to decrease thecellular concentration of these proteins. For example, proteolyticdegradation of cellular proteins is essential to normal cell function.Hijacking this process, by targeting specific disease-related proteins,presents a novel mechanism for the treatment of disease. Theirreversible nature of proteolysis makes it well-suited to serve as aregulatory switch for controlling unidirectional processes.

Ubiquitin-mediated proteolysis begins with ligation of one or moreubiquitin molecules to a particular protein substrate. Ubiquitinationoccurs through the activity of ubiquitin-activating enzymes (E1),ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3),acting sequentially to attach ubiquitin to lysine residues of substrateproteins. The E3 ligases confer specificity to ubiquitination reactionsby binding directly to particular substrates.

SUMMARY

The compounds disclosed in the present application have been discoveredto exert surprising and unexpected biological effects. In particular,the compounds disclosed in the present application modulate proteinfunction and/or modulate protein levels to restore protein homeostasis.

Some embodiments provide a compound of Formula (I), or apharmaceutically acceptable salt thereof:

wherein

R¹ is

wherein R¹ is optionally substituted with one or more R^(A);

n is 1, 2, or 3;

each R^(2a) and R^(2b) is independently H, deuterium, halogen, or C₁-C₆alkyl;

each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R^(A) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino,C₁-C₆ alkylamino, amino(C₁-C₆ alkyl), —(C═O)NR^(10a)R^(10b), (C₁-C₆alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionallysubstituted C₃-C₇ cycloalkyl;

each of R⁴, R⁵ and R⁶ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇cycloalkyl(C₁-C₃ alkyl), or optionally substituted C₃-C₇ cycloalkyl;

each of R^(7a) and R^(7b) is independently H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each of R^(8a) and R^(8b) is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl;

each of R^(9a) and R^(9b) is independently H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₇-C₁₄ aralkyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(10a) and R^(10b) is independently H or C₁-C₆ alkyl, or R^(10a)and R^(10b) together with the nitrogen atom to which they are attachedform an optionally substituted 5 or 6 membered heterocyclyl optionallysubstituted with one or more R¹¹;

each R¹¹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆alkyl, optionally substituted amino, halogen, or cyano; or two geminalR¹¹ form oxo;

Q is CH₂ or C═O;

L¹ is a bond,

wherein the asterisk * indicates the point of connection to X¹;

each of Z^(1a), Z^(1b), Z^(1c), Z^(1d), Z^(1e), and Z^(1f) isindependently a bond or —(CR^(a)R^(b))_(q1)—;

Z² is —(CR^(c)R^(d))_(q2)—;

Z³ is a bond, O or NR^(12g);

each of R^(a), R^(b), R^(c) and R^(d) is independently H, halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,or optionally substituted C₃-C₆ cycloalkyl;

each q1 and q2 is independently 1, 2 or 3;

each X^(a) and X^(b) is independently O or S;

each Ring A is independently phenyl or a five to six memberedheteroaryl, each optionally substituted with one or more R¹¹;

each of Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is —NR^(12h)—, —O—, or —S—;

each R^(12a), R^(12b), R^(12c), R^(12d), R^(12e), R^(12f), R^(12g) andR^(12h) is independently H or C₁-C₆ alkyl;

each of m1, m2, m3, m4, m5, m6, k1, k2, k3, k4, k5, k6, p1, p2, p3, p4,p5, and p6 is independently 0, 1, 2, or 3;

L² is a bond, —C(═O)—, or —(CH₂)₀₋₃—C(═O)NR¹³—; R¹³ is H or C₁-C₆ alkyl;

X¹ is alkylene or heteroalkylene; X² is —NHC(═O)—, —NH—, —O—,—NHC(═O)NH—, —NHCH₂— or —S—; and X³ is —NH—, —O—, or —S—. In someembodiments, when the compound has the structure

R¹ is

Q is C═O, n is 2, R³ is H, then R^(2a) is deuterium, halogen, or C₁-C₆alkyl.

Some embodiments provide a compound of Formula (II), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is

wherein R¹ is optionally substituted with one or more R^(A);

n is 1, 2 or 3;

each R^(2a) and R^(2b) is independently H, deuterium, halogen or C₁-C₆alkyl;

each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R^(A) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino,C₁-C₆ alkylamino, amino(C₁-C₆ alkyl), —(C═O)NR^(10a)R^(10b), (C₁-C₆alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionallysubstituted C₃-C₇ cycloalkyl;

each of R⁴ and R⁶ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇cycloalkyl(C₁-C₃ alkyl), or optionally substituted C₃-C₇ cycloalkyl;

each of R^(5a), R^(5b) and R^(5c) is independently H or C₁-C₆ alkyl;

each of R^(7a) and R^(7b) is independently H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each of R^(8a) and R^(8b) is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl;

each of R^(9a) and R^(9b) is independently H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₇-C₁₄ aralkyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(10a) and R^(10b) is independently H or C₁-C₆ alkyl, or R^(10a)and R^(10b) together with the nitrogen atom to which they are attachedform an optionally substituted 5 or 6 membered heterocyclyl optionallysubstituted with one or more R¹¹;

each R¹¹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆alkyl, optionally substituted amino, halogen, or cyano; or two geminalR¹¹ form oxo;

Q is CH₂ or C═O;

L¹ is

wherein the asterisk * indicates the point of connection to X¹;

each of Z^(1a), Z^(1b), Z^(1c), Z^(1d), Z^(1e), and Z^(1f) isindependently a bond or —(CR^(a)R^(b))_(q1)—;

Z² is —(CR^(c)R^(d))_(q2)—;

Z³ is a bond, O or NR^(12g);

each of R^(a), R^(b), R^(c) and R^(d) is independently H, halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,or optionally substituted C₃-C₆ cycloalkyl;

each q1 and q2 is independently 1, 2 or 3;

each X^(a) and X^(b) is independently O or S;

each Ring A is independently phenyl or a five to six memberedheteroaryl, each optionally substituted with one or more R¹¹;

each of Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is —NR^(12h)—, —O—, or —S—;

each R^(12a), R^(12b), R^(12c), R^(12d), R^(12e), R^(12f), R^(12g) andR^(12h) is independently H or C₁-C₆ alkyl;

each of m1, m2, m3, m4, m5, m6, k1, k2, k3, k4, k5, k6, p1, p2, p3, p4,p5, and p6 is independently 0, 1, 2, or 3;

L² is a bond, —(CH₂)₁₋₆NH—, —(CH₂)₀₋₆—C(═O)—, or —(CH₂)₀₋₃—C(═O)NR³—;

R¹³ is H or C₁-C₆ alkyl;

X¹ is alkylene or heteroalkylene; and

Ring B is phenyl or a 6 membered heteroaryl, optionally substituted withone or more R¹¹.

Some embodiments provide a pharmaceutical composition, comprising acompound of Formula (I), a compound of Formula (II), or apharmaceutically acceptable salt of any of the foregoing, and at leastone pharmaceutically acceptable excipient or carrier.

Some embodiments provide a method of decreasing cellular levels of CDK,comprising contacting a cell with an effective amount of a compound ofFormula (I), a compound of Formula (II), or a pharmaceuticallyacceptable salt of any of the foregoing. Some additional embodimentsprovide a method of inhibiting the activity of CDK in a biologicalsample, comprising contacting the biological sample with an effectiveamount of a compound of Formula (I), a compound of Formula (II), or apharmaceutically acceptable salt of any of the foregoing. In someembodiments, the CDK is CDK9 or CDK16.

Some embodiments provide a method of treating or ameliorating a disease,disorder, or condition associated with CDK, comprising administering aneffective amount of a compound of Formula (I), a compound of Formula(II), or a pharmaceutically acceptable salt of any of the foregoing, ora pharmaceutical composition of any of the foregoing, to a subject. Insome such embodiments, the disease, disorder, or condition is cancer.Some additional embodiments provide a method or treating or amelioratingcancer, comprising administering an effective amount of a compound ofFormula (I), a compound of Formula (II), or a pharmaceuticallyacceptable salt of any of the foregoing, or a pharmaceutical compositionof any of the foregoing, to a subject. In some embodiments of themethods described herein, the cancer is small cell lung cancer,non-small cell lung cancer, breast cancer, prostate cancer, head andneck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma,gastric cancer, ovarian cancer, endometrial cancer, brain cancer,retinoblastoma, leukemia, skin cancer, melanoma, squamous cellcarcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer,liver cancer, esophageal cancer, kidney carcinoma, astrogliosis,relapsed/refractory multiple myeloma, or neuroblastoma, or combinationsthereof. In some embodiments, the CDK is CDK9 or CDK16.

DETAILED DESCRIPTION

Disclosed herein are compounds useful for the treatment or ameliorationof various diseases, disorders, or conditions associated with proteinmalfunctions, including various types of cancers. In some aspects, thesecompounds are inhibitors of CDK. In some other aspects, these compoundsare inhibitors of GSPT1, CK1α, Ikaros, TNFα, or a cytokine such asIL-1β, IL-6 and IL-2. In other aspects, these compounds may also inducethe production of IL-2.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting.

While the disclosure has been illustrated and described in detail in theforegoing description, such description is to be considered illustrativeor exemplary and not restrictive. The disclosure is not limited to thedisclosed embodiments. Variations to the disclosed embodiments can beunderstood and effected by those skilled in the art in practicing theclaimed disclosure, from a study of the disclosure and the appendedclaims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

As used herein, common organic abbreviations are defined as follows:

ACN acetonitrile

AcOH acetic acid

CCl₄ carbon tetrachloride

CDI 1,1′-carbonyldiimidazole, N,N′-carbonyldiimidazole

d day, days

DCM dichloromethane, methylene chloride

DEAD diethyl azodicarboxylate

DIEA DIEA

DMA N,N-dimethylamide

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EDAC.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Ether diethyl ether

EA ethyl acetate

EtOH ethanol

K₂CO₃ potassium carbonate

LiAH lithium aluminium hydride

LiCl lithium chloride

LiOH lithium hydroxide

h hour, hours

H hydrogen atom

H₂ hydrogen gas

HCl hydrochloric acid or hydrochloride

HOBt 1-hydroxybenzotriazole

MeOH methanol

m minute, minutes

NaHCO₃ sodium bicarbonate

Na₂SO₄ sodium sulfate

NBS N-bromosuccinimide

N₂ nitrogen

Pd/C palladium on activated carbon

PE petroleum ether

RT room temperature

T3P propylphosphonic anhydride

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

quant quantitative yield

As used herein, any “R” group(s) represent substituents that can beattached to the indicated atom. An R group may be substituted orunsubstituted. If two “R” groups are described as being “taken together”the R groups and the atoms they are attached to can form a cycloalkyl,aryl, heteroaryl, or heterocycle. For example, without limitation, if R²and R³, and the atom to which it is attached, are indicated to be “takentogether” or “joined together” it means that they are covalently bondedto one another to form a ring:

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be individually and independently substitutedwith one or more group(s) individually and independently selected fromalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl,heteroaralkyl, heterocyclyl(alkyl), hydroxy, alkoxy, cycloalkoxy,aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, C-amido,N-amido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato,nitro, haloalkyl, haloalkoxy, amino, and alkylamino. When a group is notdescribed as “optionally substituted,” “unsubstituted” or “substituted,”such group is unsubstituted unless the definition of such group statesotherwise.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl group, or the number of ringatoms of a cycloalkyl, aryl, heteroaryl or heterocyclyl group. That is,the alkyl, ring of the cycloalkyl, and ring of the aryl, can containfrom “a” to “b”, inclusive, carbon atoms. Likewise, the ring of theheteroaryl and ring of the heterocyclyl can contain from “a” to “b”,inclusive, total ring atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—,CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and(CH₃)₃C—; a C₃ to C₄ cycloalkyl group refers to all cycloalkyl groupshaving from 3 to 4 carbon atoms, that is, cyclopropyl and cyclobutyl.Similarly, a “4 to 6 membered heterocyclyl” group refers to allheterocyclyl groups with 4 to 6 total ring atoms, for example,azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine,morpholine, and the like. If no “a” and “b” are designated with regardto an alkyl, cycloalkyl aryl, heteroaryl or heterocyclyl group, thebroadest range described in these definitions is to be assumed. As usedherein, the term “C₁-C₆” includes C₁, C₂, C₃, C₄, C₅ and C₆, and a rangedefined by any of the two numbers. For example, C₁-C₆ alkyl includes C₁,C₂, C₃, C₄, C₅ and C₆ alkyl, C₂-C₆ alkyl, C₁-C₃ alkyl, etc. Similarly,C₃-C₈ carbocyclyl or cycloalkyl each includes hydrocarbon ringcontaining 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by anyof the two numbers, such as C₃-C₇ cycloalkyl or C₅-C₆ cycloalkyl.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, n-propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl(straight chain or branched), and hexyl (straight chain or branched).The alkyl group may be substituted or unsubstituted.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond(s) including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Analkenyl group may be unsubstituted or substituted.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond(s) including, but not limited to, 1-propynyl,1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstitutedor substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged or spiro fashion. As used herein, the term “fused” refersto two rings which have two atoms and one bond in common. As usedherein, the term “bridged cycloalkyl” refers to compounds wherein thecycloalkyl contains a linkage of one or more atoms connectingnon-adjacent atoms. As used herein, the term “spiro” refers to two ringswhich have one atom in common and the two rings are not linked by abridge. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s), 3 to8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A cycloalkylgroup may be unsubstituted or substituted. Examples of monocycliccycloalkyl groups include, but are in no way limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.Examples of bicyclic fused cycloalkyl groups are decahydronaphthalenyl,dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples ofbicyclic bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyland norbornanyl; and examples of bicyclic spiro cycloalkyl groupsinclude spiro[3.3]heptane and spiro[4.5]decane.

As used herein, “carbocyclyl” refers to a non-aromatic a mono- ormulti-cyclic hydrocarbon ring system. When composed of two or morerings, the rings may be joined together in a fused, bridged or spirofashion, as described herein. Carbocyclyl groups can contain 3 to 30atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in thering(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). Acarbocyclyl group may be unsubstituted or substituted. Examples ofcarbocyclyl groups include, but are in no way limited to, cycloalkylgroups, as defined herein, and the non-aromatic portions of1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene,5,6,7,8-tetrahydroquinoline and 6,7-dihydro-5H-cyclopenta[b]pyridine.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆ aryl group, or a C₁₀ aryl group. Examples of aryl groupsinclude, but are not limited to, benzene and naphthalene. An aryl groupmay be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1, 2 or 3heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 5 to 10 atoms in the ring(s), 6 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms andone heteroatom; eight carbon atoms and two heteroatoms; seven carbonatoms and three heteroatoms; eight carbon atoms and one heteroatom;seven carbon atoms and two heteroatoms; six carbon atoms and threeheteroatoms; five carbon atoms and four heteroatoms; five carbon atomsand one heteroatom; four carbon atoms and two heteroatoms; three carbonatoms and three heteroatoms; four carbon atoms and one heteroatom; threecarbon atoms and two heteroatoms; or two carbon atoms and threeheteroatoms. Furthermore, the term “heteroaryl” includes fused ringsystems where two rings, such as at least one aryl ring and at least oneheteroaryl ring or at least two heteroaryl rings, share at least onechemical bond. Examples of heteroaryl rings include, but are not limitedto, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole,oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine,pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnolineand triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” refers to three-, four-, five-, six-,seven-, eight-, nine-, and ten-membered monocyclic, bicyclic andtricyclic ring system wherein carbon atoms together with from 1 to 5heteroatoms constitute said ring system. A heterocycle may optionallycontain one or more unsaturated bonds situated in such a way, however,that a fully delocalized pi-electron system does not occur throughoutall the rings (i.e., heterocyclyl groups are not aromatic). Theheteroatom(s) is an element other than carbon including, but not limitedto, oxygen, sulfur and nitrogen. A heterocycle may further contain oneor more carbonyl functionalities, so as to make the definition includeoxo-systems such as lactams, lactones, and cyclic carbamates. Whencomposed of two or more rings, the rings may be joined together in afused, bridged or spiro fashion. As used herein, the term “fused” refersto two rings which have two atoms and one bond in common. As usedherein, the term “bridged heterocyclyl” refers to compounds wherein theheterocyclyl contains a linkage of one or more atoms connectingnon-adjacent atoms. As used herein, the term “spiro” refers to two ringswhich have one atom in common and the two rings are not linked by abridge. Heterocyclyl groups can contain 3 to 10 atoms in the ring(s), 3to 8 atoms in the ring(s), 3 to 6 atoms in the ring(s), or 5 to 6 atomsin the ring(s). For example, five carbon atoms and one heteroatom; fourcarbon atoms and two heteroatoms; three carbon atoms and threeheteroatoms; four carbon atoms and one heteroatom; three carbon atomsand two heteroatoms; two carbon atoms and three heteroatoms; one carbonatom and four heteroatoms; three carbon atoms and one heteroatom; or twocarbon atoms and one heteroatom. Additionally, any nitrogens in aheterocyclyl group may be quaternized. Heterocyclyl groups can be linkedto the rest of the molecule via a carbon atom in the heterocyclyl group(C-linked) or by a heteroatom in the heterocyclyl group, such as anitrogen atom (N-linked). Heterocyclyl groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” groups include but are notlimited to, aziridine, oxirane, thiirane, azetidine, oxetane,1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane,1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane,1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine,2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacid, dioxopiperazine, hydantoin, dihydrouracil, trioxane,hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline,isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine,piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione,4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine,tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine,thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fusedanalogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane,2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane,2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

“Alkylene groups” are straight chained or branched saturated all-carbontethering groups, forming bonds to connect molecular fragments via theirterminal carbon atoms. Alkylene groups contain from 2 to 8 carbon atoms.Examples include but are not limited to ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), and pentylene(—CH₂CH₂CH₂CH₂CH₂—).

As used herein, “heteroalkylene” refers to an alkylene group, as definedherein, containing one or more heteroatoms in the carbon back bone(i.e., an alkylene group in which one or more carbon atoms is replacedwith a heteroatom). Heteroalkylene groups include, but are not limitedto ether, thioether, amino-alkylene, and alkylene-amino-alkylenemoieties.

As used herein, “lower alkylene groups” are straight-chained —CH₂—tethering groups, forming bonds to connect molecular fragments via theirterminal carbon atoms. Lower alkylene groups contain from 1 to 4 carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—).

As used herein, “cycloalkylalkyl” and “cycloalkyl(alkyl)” refer to acycloalkyl group (as defined herein) connected, as a substituent, via alower alkylene group. Examples include but are not limited tocyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, andcyclohexylpropyl.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylgroup, as defined herein. A non-limiting list of alkoxys is methoxy,ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy,sec-butoxy, and tert-butoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

The terms “amino” or “optionally substituted amino,” as used hereinrefer to a —NR_(A)R_(B) radical where R_(A) and R_(B) are independentlyhydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined herein. An unsubstituted amino groups isan —NH₂ group.

As used herein, “alkylamino” or “(alkyl)amino” refers to a —NR_(A)R_(B)group where R_(A) and R_(B) are hydrogen or alkyl as defined above, andat least one of R_(A) and R_(B) is alkyl. The alkyl portion of the(alkyl)amine, includes, for example, C₁-C₆ alkyl groups. Examples ofalkylamino groups include, but are not limited to methylamino (—NHMe),ethylamino (—NHEt), dimethylamino (—N(Me)₂, methylethylamino(—N(Me)(Et)), and isopropylamino (—NHiPr).

As used herein, “aminoalkyl” or “amino(alkyl)” refers to an alkyl groupin which one or more of the hydrogen atoms are replaced by an aminogroup or “—NR_(A)R_(B)” group as defined herein. The alkyl portion ofthe amino(alkyl), includes, for example, C₁-C₆ alkyl. Examples ofaminoalkyl groups include, but are not limited to —(CH₂)₁₋₄NH₂,—(CH₂)₁₋₄—NHCH₃, —(CH₂)₁₋₄—NHC₂H₅, —(CH₂)₁₋₄—N(CH₃)₂,—(CH₂)₁₋₄—N(C₂H₅)₂, —(CH₂)₁₋₄—NH—CH(CH₃)₂, —(CH₂)₁₋₄N(CH₃)C₂H₅, and—CH(NH₂)CH₃.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine, and iodine.

As used herein, “alkoxyalkyl” or “(alkoxy)alkyl” refers to an alkoxygroup connected via an lower alkylene group, such as C₂-C₈ alkoxyalkyl,or (C₁-C₆ alkoxy)C₁-C₆ alkyl, for example, —(CH₂)₁₋₃—OCH₃.

As used herein, “—O-alkoxyalkyl” or “—O-(alkoxy)alkyl” refers to analkoxy group connected via an —O-(lower alkylene) group, such as—O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, for example, —O—(CH₂)₁₋₃—OCH₃.

Where the numbers of substituents is not specified (e.g., haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two, or three atoms.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, or maybe stereoisomeric mixtures, and include all diastereomeric, andenantiomeric forms. In addition it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Stereoisomers are obtained,if desired, by methods such as, stereoselective synthesis and/or theseparation of stereoisomers by chiral chromatographic columns.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.In addition, if a group or substituent is depicted as

and when L is defined as a bond; such group or substituent is equivalentto

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensand/or deuteriums.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriummay afford certain therapeutic advantages from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,reference herein to a compound encompasses all potential isotopic formsunless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of pharmaceutically acceptable salts and/or conformersof compounds of preferred embodiments, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of molecules with the same structuralformula but different conformations (conformers) of atoms about arotating bond. Likewise, it is understood that the compounds describedherein, include the compound in any of the forms described herein (e.g.,pharmaceutically acceptable salts, enantiomeric forms, tautomeric forms,and the like).

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl(BOC), acetyl, or isobutyryl); arylalkylcarbonyls (e.g.,benzyloxycarbonyl or benzoyl); substituted methyl ether (e.g.,methoxymethyl ether); substituted ethyl ether; a substituted benzylether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl); esters (e.g., benzoate ester); carbonates (e.g.,methoxymethylcarbonate); sulfonates (e.g., tosylate or mesylate);acyclic ketal (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxaneor 1,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal;cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or1,3-dithiolane); and triarylmethyl groups (e.g., trityl;monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); or4,4′,4″-trimethoxytrityl (TMTr)).

The term “leaving group” as used herein refers to any atom or moietythat is capable of being displaced by another atom or moiety in achemical reaction. More specifically, in some embodiments, “leavinggroup” refers to the atom or moiety that is displaced in a nucleophilicsubstitution reaction. In some embodiments, “leaving groups” are anyatoms or moieties that are conjugate bases of strong acids. Examples ofsuitable leaving groups include, but are not limited to, tosylates andhalogens. Non-limiting characteristics and examples of leaving groupscan be found, for example in Organic Chemistry, 2d ed., Francis Carey(1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., AndrewStreitwieser and Clayton Heathcock (1981), pages 169-171; and OrganicChemistry, 5^(th) ed., John McMurry (2000), pages 398 and 408; all ofwhich are incorporated herein by reference for the limited purpose ofdisclosing characteristics and examples of leaving groups.

The term “pharmaceutically acceptable salt” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic acid, acetic acid (AcOH),propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid,fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid,mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid,ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearicacid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid,valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonicacid. Pharmaceutical salts can also be obtained by reacting a compoundwith a base to form a salt such as an ammonium salt, an alkali metalsalt, such as a lithium, sodium or a potassium salt, an alkaline earthmetal salt, such as a calcium, magnesium or aluminum salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, (C₁-C₇ alkyl)amine, cyclohexylamine,dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, tromethamine, and salts with aminoacids such as arginine and lysine; or a salt of an inorganic base, suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, or the like. In some embodiments, thecompounds described herein may be in the form of a trifluoroacetatesalt.

The term “CDK protein,” as used herein, refers to a protein in thecyclin-dependent kinase family, including, but not limited to CDK1,CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12,CDK13, CDK14, CDK15, and CDK16.

The terms “effective amount” and “therapeutically effective amount” arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount of an agent or a compound being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case may be determined using techniques, suchas a dose escalation study. Where a drug has been approved by the U.S.Food and Drug Administration (FDA) or a counterpart foreign medicinesagency, a “therapeutically effective amount” optionally refers to thedosage approved by the FDA or its counterpart foreign agency fortreatment of the identified disease or condition.

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition to a subject forprophylactic and/or therapeutic purposes. The term “prophylactictreatment” refers to treating a subject who does not yet exhibitsymptoms of a disease or condition, but who is susceptible to, orotherwise at risk of, a particular disease or condition, whereby thetreatment reduces the likelihood that the patient will develop thedisease or condition. The term “therapeutic treatment” refers toadministering treatment to a subject already suffering from a disease orcondition.

The terms “co-administration” and similar terms as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toadministration of the selected therapeutic agents to a single patient,and are intended to include treatment regimens in which the agents areadministered by the same or different route of administration or at thesame or different time.

Compounds

Formula (I)

Some embodiments provide a compound of Formula (I), or apharmaceutically acceptable salt thereof as described herein:

In some embodiments, when the compound has the structure of Formula (A):

R¹ is

Q is C═O, n is 2, R³ is H, then R^(2a) is deuterium, halogen, or C₁-C₆alkyl. In some further embodiments, when the compound is Formula (A), R¹is

R³ is H; then n is 1 or 3. In some further embodiments, when thecompound has the structure of Formula (A), then R¹ is

In some embodiments of the compound of Formula (I), R⁴ is H.

In some further embodiments, the compound of Formula (I) is alsorepresented by Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is

R^(2a) is H, deuterium, fluoro, or methyl; n is 1, 2, or 3; each of mand p is independently 1, 2, 3, 4, or 5; X¹ is an unsubstituted alkyleneor an unsubstituted heteroalkylene; X² is —(CO)NH—, —NH(CO)—, —NH—, —O—,—NH(CO)NH—, —NHCH₂—, —CH₂NH—, or —S—; X³ is —NH—, —O—, or —S—; and R⁵and R⁶ are independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₃-C₆ cycloalkyl(C₁-C₃ alkyl), C₃-C₆ cycloalkyl or C₁-C₆ haloalkoxy. Insome embodiments, m is 1; and p is 1. In other embodiments, m is 1; andp is 2. In still other embodiments, m is 2; and p is 2.

In some embodiments of the compounds of Formula (I) or (Ia), one of R⁵and R⁶ is H and the other of R⁵ and R⁶ is C₁-C₆ alkyl (for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl(straight chain or branched), or hexyl (straight chain or branched)),C₁-C₆ haloalkyl (for example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, and —CF₂Cl),C₁-C₆ alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, t-butoxy, pentoxy (straight chain or branched), orhexoxy (straight chain or branched)), optionally substituted C₃-C₇cycloalkyl(C₁-C₃ alkyl) (for example, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, or cyclohexylethyl, halogensubstituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl) (e.g., fluoro substitutedcyclopropyl(C₁-C₃ alkyl) such as

or C₁-C₆ haloalkyl substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl) (e.g.,trifluoromethyl substituted cyclopropyl(C₁-C₃ alkyl) such as

optionally substituted C₃-C₇ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, halogen substituted C₃-C₇cycloalkyl (e.g., fluoro substituted cyclopropyl such as

or C₁-C₆ haloalkyl substituted C₃-C₇ cycloalkyl (e.g., trifluoromethylsubstituted cyclopropyl such as

or C₁-C₆ haloalkoxy (for example, —OCH₂F, —OCHF₂, a —OCF₃, —OCH₂CF₃, and—OCF₂Cl). In some embodiments, one of R⁵ and R⁶ is H and the other of R⁵and R⁶ is C₂-C₄ alkyl, C₂-C₄ haloalkyl, C₂-C₄ alkoxy, or C₂-C₄haloalkoxy. In some embodiments, one of R⁵ and R⁶ is H and the other ofR⁵ and R⁶ is C₁-C₆ alkyl. In some embodiments, R⁵ is H and R⁶ is C₁-C₆alkyl (e.g., t-butyl). In other embodiments, R⁵ is C₁-C₆ alkyl (e.g.,t-butyl) and R⁶ is H. In some embodiments, one of R⁵ and R⁶ is H and theother of R⁵ and R⁶ is trifluoromethyl fluoro substituted cyclopropyl orcyclopropyl(C₁-C₃ alkyl), such as

In some embodiments of the compounds of Formula (I) or (Ia), X³ is —NH—.In other embodiments, X³ is —O—. In still other embodiments, X³ is —S—.

In some embodiments of the compounds of Formula (I) or (Ia), X² is—NH(CO)—. In some such embodiment, X² may connect to the adjacentthiazole moiety in either direction (i.g., either via the amine or thecarbonyl). In other embodiments, X² is —NH—. In some embodiments, X² is—O—. In other embodiments, X² is-NH(CO)NH—. In still other embodiments,X² is —NHCH₂—. In other embodiments, X² is —S—.

In some embodiments, the compound of Formula (I) is also represented byFormula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R¹, X¹, L¹ and L²are defined herein in Formula (I).

In some embodiments of the compounds of Formula (I) or (Ib), R¹ isunsubstituted. In other embodiments, R¹ is substituted with one or moreR^(A). In some further embodiments, R^(A) is substituted at thethiophene moiety, isoindolinone moiety, or isoindolinedione moiety ofR¹. In some further embodiments, R¹ is

In other embodiments, R¹ is

In still other embodiments, R¹ is

In some embodiments, wherein R¹ is

In some further embodiments, R¹ is substituted with one R^(A), forexample, R¹ is

In some embodiments, R^(A) is halogen (e.g., fluoro). In someembodiments, R³ is H.

In some embodiments of the compounds of Formula (I), (Ia) or (Ib),R^(2a) is H. In other embodiments, R^(2a) is deuterium, fluoro ormethyl. In some embodiments of the compounds of Formula (I) or (Ib),R^(2b) is C₁-C₆ alkyl, for example, methyl, ethyl or isopropyl. In oneembodiment, R^(2b) is H. In another embodiment, R^(2b) is methyl.

In some embodiments of the compounds of Formula (I), (Ia) or (Ib), nis 1. In other embodiments, n is 2. In still other embodiments, n is 3.

In some embodiments of the compounds of Formula (I), (Ia) or (Ib), X¹ isan alkylene, for example, C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂, C₁₃, C₁₄, or C₁₅ alkylene (including both straight-chained orbranched). In some embodiments, X¹ is methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, or octylene. In some suchembodiments, X¹ is unsubstituted. In some other embodiments, X¹ isheteroalkylene (including both straight-chained or branched), forexample C₁-C₁₅ alkylene where one or more carbon atoms (includinghydrogen atom(s) attached to the carbon atom) are replaced by aheteroatom. In some instances, the heteroatom in the heteroalkylenecontains oxygen, nitrogen or sulfur, or combinations thereof. In somesuch embodiments, X¹ is a heteroalkylene containing carbon, hydrogen andoxygen atoms (where at least one methylene unit is replaced by oxygen),such as [—(CH₂)₂O-]₁₋₅ or —[(CH₂)₂O]₁₋₅(CH₂)₂—. In other embodiments, X¹is a heteroalkylene containing carbon, hydrogen and nitrogen atoms(where at least one methylene unit is replaced by NR¹⁴; such as—(CH₂)₁₋₅—NR¹⁴—(CH₂)₁₋₅—, and wherein R¹⁴ is H or C₁-C₆ alkyl (e.g.,methyl). In one embodiment, R¹⁴ is methyl. In still other embodiments,X¹ is an unsubstituted heteroalkylene containing carbon, hydrogen,oxygen, and nitrogen atoms. In some embodiments, X¹ is —CH₂CH₂O—,—(CH₂CH₂O)₂—, —(CH₂CH₂O)₃—, —CH₂CH₂OCH₂CH₂—, —(CH₂CH₂O)₂CH₂CH₂—,—(CH₂CH₂O)₃CH₂CH₂—, —(CH₂CH₂O)₄CH₂CH₂—, —CH₂NR¹⁴CH₂—,—CH₂CH₂NR¹⁴CH₂CH₂—, —(CH₂)₂OCH₂(CH₂)₃—, or —(CH₂)₃NR¹⁴(CH₂)₃—. In somesuch embodiments, R¹⁴ is H or methyl.

In some embodiments of the compounds of Formula (I) or (Ib), L¹ is

In some such embodiments, each of R^(12a) and R^(12b) is H; X^(a) is O;Z^(1a) is a bond or —(CH₂)₁₋₃—; and m1 is 0 or 1. In other embodiments,L¹ is

In some such embodiments, each of R^(12c) and R^(12d) is H; X^(a) is O;Z² is —CH₂—; Z^(1b) is a bond or —(CH₂)₁₋₃—; and m2 is 0 or 1. In otherembodiments, L¹ is *—Z^(1e)—Z³—(CH₂)_(m5)—, and wherein Z³ is O orNR^(12g). In some such embodiments, Z³ is NR^(12g); R^(12g) is H; Z^(1e)is a bond or —(CH₂)₁₋₃—; and m5 is 0 or 1. In other embodiments, L¹ is

In some such embodiments, R^(12f) is H; Z^(1d) is a bond or —(CH₂)₁₋₃—;X^(a) is O; Ring A is phenyl; Y⁴ is —O— or —NH—; each of k4, p4 and m4is independently 0 or 1. In other embodiments, L¹ is

and wherein Z³ is O or NR^(12g). In some such embodiments, Z³ isNR^(12g); R^(12g) is H; Z^(1e) is a bond or —(CH₂)₁₋₃—; Ring A isphenyl; Y⁵ is —O— or —NH—; each of k5, p5 and m5 is independently 0or 1. In some other such embodiments, Z³ is a bond; Z^(1e) is a bond or—(CR^(a)R^(b))₁₋₃—; and m5 is 0. In still other embodiments, L¹ is

In some such embodiments, Z^(1f) is a bond or —(CH₂)₁₋₃—; m6 is 0 or 1.In any embodiments of L¹ that contains Ring A, Ring A may be optionallysubstituted with one or more R¹¹. Additional non-limiting examples of L¹include *—NHC(═O)NHCH₂—, *—NHCH₂C(═O)NHCH₂—, —NH—, *—NHCH₂—,

In some embodiments, * indicates the point of connection to X¹.

In some embodiments of the compounds of Formula (I) or (Ib), L² is abond. In other embodiments, L² is —C(═O)—. In other embodiments, L² is—CH₂—C(═O)NR¹³—. In some further embodiments, L² is —CH₂—C(═O)NH—**where ** indicates the point of connection to X¹.

In some embodiments of the compounds of Formula (I) or (Ib), R¹ is

n is 2; and -L²-X¹-L¹-is listed in Table A. In other embodiments, R¹ is

n is 2 or 3; and -L²-X¹-L¹-is listed in Table A. In other embodiments,R¹ is

n is 2; and -L²-X¹-L¹-is listed in Table A.

TABLE A

Additional exemplary embodiments of the compound of Formula (I) isselected from the group consisting of: 1-3, 6, 7, 11-15, 18-20, 26, 27,33, 34, 41, 42, 44, 47, 52, 54, 57 and 58 of Table B, or apharmaceutically acceptable salt thereof.

Formula (II)

Some embodiments provide a compound of Formula (II), or apharmaceutically acceptable salt as described herein:

In some further embodiments, the compound of Formula (II) is alsorepresented by Formula (II′):

or a pharmaceutically acceptable salt thereof.

In some further embodiments, the compound of Formula (II) is alsorepresented by Formula (IIa):

wherein:

R¹ is

R^(2a) is H or deuterium; n is 1, 2, or 3; q is 1, 2, 3, 4, or 5; X¹ isan unsubstituted alkylene or an unsubstituted heteroalkylene; X² is abond, —(CH₂)₁₋₆NH—, —CH₂—, —CH₂CH₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— or—(CH₂)₆—; Ring B is phenyl or 6 membered heteroaryl, optionallysubstituted with one to five substituents selected from the groupconsisting of halogen and C₁-C₆ alkyl; R⁴ and R⁶ are independently H,C₁-C₆ alkyl, or C₃-C₇ cycloalkyl(alkyl); and R^(5a) is H or C₁-C₆ alkyl.In some further embodiments, q is 1.

In some embodiments of Formula (II), (II′) or (IIa), Ring B is phenyl.In other embodiments, Ring B is a 6 membered heteroaryl containing 1nitrogen atom. In other embodiments, Ring B is a 6 membered heteroarylcontaining 2 nitrogen atoms. In other embodiments, Ring B is a 6membered heteroaryl containing 3 nitrogen atoms. In some embodiments,Ring B is a pyridine. In other embodiments, Ring B is a pyrimidine. Inother embodiments, Ring B is triazine. Ring B may be optionallysubstituted with one or more R¹¹. In some embodiments, Ring B is

each optionally substituted with one R¹¹. In some further embodiments,Ring B is

In some such embodiments, Ring B is

where ** indicate the point of attachment to

In some such embodiments, Ring B is unsubstituted. In other embodiments,R¹¹ is independently halogen (such as chloro or fluoro) or C₁-C₆ alkyl(e.g., methyl).

In some embodiments of Formula (II), (II′) or (IIa), at least one of R⁴and R⁶ is H. In other embodiments, one of R⁴ and R⁶ is H and the otherof R⁴ and R⁶ is halogen, C₁-C₆ alkyl (for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl (straight chainor branched), or hexyl (straight chain or branched)), C₁-C₆ haloalkyl(for example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, and —CF₂Cl), C₁-C₆ alkoxy(for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, t-butoxy, pentoxy (straight chain or branched), or hexoxy(straight chain or branched)), optionally substituted C₃-C₇cycloalkyl(C₁-C₃ alkyl) (for example, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, halogen substitutedC₃-C₇ cycloalkyl(C₁-C₃ alkyl) (e.g., fluoro substitutedcyclopropyl(C₁-C₃ alkyl) such as

or C₁-C₆ haloalkyl substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl) (e.g.,trifluoromethyl substituted cyclopropyl(C₁-C₃ alkyl) such as

optionally substituted C₃-C₇ cycloalkyl (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, halogen substituted C₃-C₇cycloalkyl (e.g., fluoro substituted cyclopropyl such as

or C₁-C₆ haloalkyl substituted C₃-C₇ cycloalkyl (e.g., trifluoromethylsubstituted cyclopropyl such as

or C₁-C₆ haloalkoxy (for example, —OCH₂F, —OCHF₂, —OCF₃, —OCH₂CF₃, and—OCF₂Cl). In still other embodiments, one of R⁴ and R⁶ is H and theother R⁴ and R⁶ is C₃-C₇ cycloalkyl(C₁-C₂ alkyl), e.g.,cyclopropyl(C₁-C₂ alkyl), cyclobutyl(C₁-C₂ alkyl), cyclopentyl(C₁-C₂alkyl), or cyclohexyl(C₁-C₂ alkyl). In further embodiments, R⁴ is H andR⁶ is cyclopropyl(C₁-C₃ alkyl), e.g., —(CH₂)-cyclopropyl. In someembodiments, one of R⁴ and R⁶ is H and the other R⁴ and R⁶ istrifluoromethyl or fluoro substituted cyclopropyl or cyclopropyl(C₁-C₃alkyl), such as

In some embodiments of Formula (II), (II′) or (IIa), R^(5a) is H. Inother embodiments, R^(5a) is C₁-C₆ alkyl. In some embodiments, R^(5a) ismethyl.

In some embodiments of Formula (II) or (II′), each of R^(5b) and R^(5c)is H. In other embodiments, at least one of R^(5b) and R^(5c) is C₁-C₆alkyl. In some embodiments, one of R^(5b) and R^(5c) is R^(5b) ismethyl.

In some embodiments, the compound of Formula (II) is also represented byFormula (IIb):

or a pharmaceutically acceptable salt thereof, wherein R¹, X¹, L¹ and L²are defined herein in Formula (I); and R¹¹ is halogen (e.g., F or Cl).In some further embodiments, the compound of Formula (IIb) is alsorepresented by Formula (IIb′):

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula (II), (II′), (IIb) or(IIb′), R¹ is unsubstituted. In other embodiments, R¹ is substitutedwith one or more R^(A). In some further embodiments, R^(A) issubstituted at the thiophene moiety, isoindolinone moiety, orisoindolinedione moiety of R¹. In some further embodiments, R¹ is

In other embodiments, R¹ is

In still other embodiments, R¹ is

In some embodiments, wherein R¹ is

In some further embodiments, R¹ is substituted with one R^(A), forexample, R¹ is

In some embodiments, R^(A) is halogen (e.g., fluoro). In someembodiments, R³ is H.

In some embodiments of the compounds of Formula (II), (II′), (IIa),(IIb) or (IIb′), R^(2a) is H. In other embodiments, R^(2a) is deuterium.In other embodiments, R^(2a) is fluoro or methyl. In some embodiments ofthe compounds of Formula (I) or (Ib), R^(2b) is C₁-C₆ alkyl, forexample, methyl, ethyl or isopropyl. In one embodiment, R^(2b) is H. Inanother embodiment, R^(2b) is methyl.

In some embodiments of the compounds of Formula (II), (II′), (IIa),(IIb) or (IIb′), n is 1. In other embodiments, n is 2. In still otherembodiments, n is 3.

In some embodiments of the compounds of Formula (II), (II′), (IIa),(IIb) or (IIb′), X¹ is an alkylene, for example, C₁, C₂, C₃, C₄, C₅, C₆,C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, or C₁₅ alkylene (including bothstraight-chained or branched). In some embodiments, X¹ is methylene,ethylene, propylene, butylene, pentylene, hexylene, heptylene, oroctylene. In some such embodiments, X¹ is unsubstituted. In some otherembodiments, X¹ is heteroalkylene (including both straight-chained orbranched), for example C₁-C₁₅ alkylene where one or more carbon atoms(including hydrogen atom(s) attached to the carbon atom) are replaced bya heteroatom. In some instances, the heteroatom in the heteroalkylenecontains oxygen, nitrogen or sulfur, or combinations thereof. In somesuch embodiments, X¹ is a heteroalkylene containing carbon, hydrogen andoxygen atoms (where at least one methylene unit is replaced by oxygen),such as [—(CH₂)₂O-]₁₋₅ or —[(CH₂)₂O]₁₋₅(CH₂)₂—. In other embodiments, X¹is a heteroalkylene containing carbon, hydrogen and nitrogen atoms(where at least one methylene unit is replaced by NR¹⁴; such as—(CH₂)₁₋₅—NR¹⁴—(CH₂)₁₋₅—, and wherein R¹⁴ is H or C₁-C₆ alkyl (e.g.,methyl). In one embodiment, R¹⁴ is methyl. In still other embodiments,X¹ is an unsubstituted heteroalkylene containing carbon, hydrogen,oxygen, and nitrogen atoms. In some embodiments, X¹ is —CH₂CH₂O—,—(CH₂CH₂O)₂—, —(CH₂CH₂O)₃—, —CH₂CH₂OCH₂CH₂—, —(CH₂CH₂O)₂CH₂CH₂—,—(CH₂CH₂O)₃CH₂CH₂—, —(CH₂CH₂O)₄CH₂CH₂—, —CH₂NR¹⁴CH₂—,—CH₂CH₂NR¹⁴CH₂CH₂—, —(CH₂)₂OCH₂(CH₂)₃—, or —(CH₂)₃NR¹⁴(CH₂)₃—. In somesuch embodiments, R¹⁴ is H or methyl.

In some embodiments of the compounds of Formula (II), (II′), (IIb) or(IIb′), L¹ is

n some such embodiments, each of R^(12a) and R^(12b) is H; X^(a) is O;Z^(1a) is a bond or —(CH₂)₁₋₃—; and m1 is 0 or 1. In other embodiments,L¹ is

In some such embodiments, each of R^(12c) and R^(12d) is H; X^(a) is O;Z² is —CH₂—; Z^(1b) is a bond or —(CH₂)₁₋₃—; and m2 is 0 or 1. In otherembodiments, L¹ is

In some such embodiments, each of R^(12c) and R^(12d) is H; X^(a) is O;Z^(1b) is a bond or —(CH₂)₁₋₃—; Z² is —(CH₂)₁₋₃—; Ring A is phenyl; andeach of k2, p2 and m2 is independently 0 or 1. In other embodiments, L¹is *—Z^(1e)—Z³—(CH₂)_(m5)— and wherein Z³ is O or NR^(12g). In some suchembodiments, Z³ is NR^(12g); R^(12g) is H; Z^(1e) is a bond or—(CH₂)₁₋₃—; and m5 is 0 or 1. In other embodiments, L¹ is

In some such embodiments, R^(12f) is H; Z^(1d) is a bond or —(CH₂)₁₋₃—;X^(a) is O; Ring A is phenyl; Y⁴ is —O— or —NH—; each of k4, p4 and m4is independently 0 or 1. In other embodiments, L¹ is

and wherein Z³ is O or NR^(12g). In some such embodiments, Z³ isNR^(12g); R^(12g) is H; Z^(1e) is a bond or —(CH₂)₁₋₃—; Ring A isphenyl; Y⁵ is —O— or —NH—; each of k5, p5 and m5 is independently 0or 1. In some other such embodiments, Z³ is a bond; Z^(1e) is a bond or—(CR^(a)R^(b))₁₋₃—; and m5 is 0. In still other embodiments, L¹ is

In some such embodiments, Z^(1f) is a bond or —(CH₂)₁₋₃—; m6 is 0 or 1.In any embodiments of L¹ that contains Ring A, Ring A may be optionallysubstituted with one or more R¹¹. Additional non-limiting examples of L¹include *—NHC(═O)NHCH₂—, *—NHCH₂C(═O)NHCH₂—, —NH—, *—NHCH₂—,

In some embodiments, * indicates the point of connection to X¹.

In some embodiments of the compounds of Formula (II), (II′), (IIb) or(IIb′), L² is a bond. In other embodiments, L² is —C(═O)—. In otherembodiments, L² is —CH₂—C(═O)NR¹³—. In some further embodiments, L² is—CH₂—C(═O)NH—** where ** indicates the point of connection to X¹.

In some embodiments of the compounds of Formula (II), (II′), (IIa),(IIb) or (IIb′), R¹ is

n is 2; -L²-X¹-L¹- and is listed in Table A. In other embodiments, R¹ is

n is 2 or 3; and -L²-X¹-L¹-is listed in Table A. In other embodiments,R¹ is

n is 2; and -L²-X¹-L¹-is listed in Table A.

In some embodiments, the compound of Formula (II) is selected from thegroup consisting of Compounds 4, 5, 8, 9, 16, 17, 21-25, 28-32, 35-40,43, 45, 46, 48-51, 53, 55, 56 and 59-72 of Table B, or apharmaceutically acceptable salt thereof.

Uses or Methods of Treatment

Some embodiments provide a method of inhibiting the activity of aprotein in a biological sample, comprising contacting an effectiveamount of a compound of Formula (I) (including (Ia) and (Ib)), acompound of Formula (II) (including (II′), (IIa), (IIb) and (IIb′)), ora pharmaceutically acceptable salt thereof with one or more cells in thebiological sample. Some embodiments provide the use of a compound ofFormula (I) (including (Ia) and (Ib)), a compound of Formula (II)(including (II′), (IIa), (IIb) and (IIb′)) or a pharmaceuticallyacceptable salt thereof, for inhibiting the activity of a protein in abiological sample, comprising contacting an effective amount of thecompound or the pharmaceutically salt thereof with one or more cells inthe biological sample. In some embodiments, the protein is CDK, GSPT1,CK1α, Ikaros, TNFα, or a cytokine such as IL-1β, IL-2 and IL-6. In somefurther embodiments, the protein is a CDK protein, for example, CDK9 orCDK16.

Some embodiments provide a method of decreasing cellular levels of aprotein, comprising contacting one or more cells with an effectiveamount a compound of Formula (I) (including (Ia) and (Ib)), a compoundof Formula (II) (including (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof. Some embodiments provide theuse of a compound of Formula (I) (including (Ia) and (Ib)), a compoundof Formula (II) (including (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof for decreasing cellular levelsof a CDK, comprising contacting one or more cells with an effectiveamount of the compound or the pharmaceutical salt thereof. In someembodiments, the protein is CDK, GSPT1, CK1α, Ikaros, TNFα, or acytokine such as IL-1β, IL-2 and IL-6. In some further embodiments, theprotein is a CDK protein, for example, CDK9 or CDK16.

Additional embodiments provide a method of inducing the activity ofIL-2, comprising contacting one or more cells with an effective amountof a compound of Formula (I) (including (Ia) and (Ib)), a compound ofFormula (II) (including (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof. Other embodiments provide amethod of increasing the cellular levels of IL-2, comprising contactinga cell with an effective amount a compound of Formula (I) (including(Ia) and (Ib)), a compound of Formula (II) (including (II′), (IIa),(IIb) and (IIb′)), or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods or the uses described herein, thecell is a cancer cell. The cancer cell may be selected from the groupconsisting of small cell lung cancer cell, non-small cell lung cancercell, breast cancer cell, prostate cancer cell, head and neck cancercell, pancreatic cancer cell, colon cancer cell, rectal cancer cell,teratoma cell, gastric cancer cell, ovarian cancer cell, endometrialcancer cell, brain cancer cell, retinoblastoma cell, leukemia cell, skincancer cell, melanoma cell, squamous cell carcinoma cell, liposarcomacell, lymphoma cell, multiple myeloma cell, testicular cancer cell,liver cancer cell, esophageal cancer cell, kidney carcinoma cell,astrogliosis cell, relapsed/refractory multiple myeloma cell, andneuroblastoma cell. In some further embodiments, the cancer cell isleukemia cell, lymphoma cell or multiple myeloma cell (includingrelapsed/refractory).

Some embodiments provide a method of treating or ameliorating a disease,disorder, or condition associated with a protein malfunction in asubject; the method comprising administering a therapeutically effectiveamount of a compound of Formula (I) (including (Ia) and (Ib)), acompound of Formula (II) (including (II′), (IIa), (IIb) and (IIb′)), ora pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof to the subject; wherein the disease, disorder, orcondition is cancer. Some embodiments provide the use of a compound ofFormula (I) (including (Ia) and (Ib)), a compound of Formula (II)(including (II′), (IIa), (IIb) and (IIb′)), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof fortreating or ameliorating a disease, disorder, or condition associatedwith a protein malfunction; wherein the disease, disorder, or conditionis cancer. In some embodiments, the protein is CDK, GSPT1, CK1α, Ikaros,TNFα, or a cytokine such as IL-1β, IL-2 and IL-6. In some furtherembodiments, the protein is a CDK protein, for example, CDK9 or CDK16.

Some embodiments provide a method of treating or ameliorating cancer ina subject, comprising administering a therapeutically effective amountof a compound of Formula (I) (including (Ia) and (Ib)), a compound ofFormula (II) (including (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof to the subject. Some embodiments provide the use ofa compound of Formula (I) (including (Ia) and (Ib)), a compound ofFormula (II) (including (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof for treating or ameliorating cancer. In someembodiments, the cancer is associated with one or more proteinmalfunction, including CDK, GSPT1, CK1α, Ikaros, TNFα, or a cytokinesuch as IL-1β, IL-2 and IL-6. In some further embodiments, the cancer isassociated with a CDK protein.

In any embodiments of the methods or uses described herein, the cancermay include small cell lung cancer, non-small cell lung cancer, breastcancer, prostate cancer, head and neck cancer, pancreatic cancer, coloncancer, rectal cancer, teratoma, gastric cancer, ovarian cancer,endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer,melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiplemyeloma, testicular cancer, liver cancer, esophageal cancer, kidneycarcinoma, astrogliosis, relapsed/refractory multiple myeloma, orneuroblastoma. In some further embodiments, the cancer is leukemia,lymphoma, or multiple myeloma (including relapsed/refractory).

In any embodiments of the methods or uses described herein, the CDKprotein is CDK1. In other embodiments, the CDK protein is CDK2. In stillother embodiments, the CDK protein is CDK4. In some embodiments, the CDKprotein is CDK5. In some embodiments, the CDK protein is CDK6. In otherembodiments, the CDK protein is CDK9. In some other embodiments, the CDKprotein is CDK16. In still other embodiments, the CDK protein is acombination of one or more of CDK proteins. In some embodiments, the CDKprotein is wild-type. In other embodiments, the CDK protein is a mutantform of the CDK protein. In some embodiments, the CDK protein isoverexpressed.

Some embodiments provide a method of treating, ameliorating, orpreventing an inflammatory disease, disorder or condition in a subject,comprising administering a therapeutically effective amount of acompound of Formula (I) (including (Ia) and (Ib)), a compound of Formula(II) (including (II′), (IIa), (IIb) and (IIb′)), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof to thesubject. Some embodiments provide the use of a compound of Formula (I)(including (Ia) and (Ib)), a compound of Formula (II) (including (II′),(IIa), (IIb) and (IIb′)), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof for treating, ameliorating, orpreventing an inflammatory disease, disorder or condition. In someembodiments, the inflammatory disease, disorder or condition is aneurodegenerative disease (such as multiple sclerosis, Alzheimer'sdisease, Parkinson's disease), fibrosis (such as pulmonary fibrosis),lupus, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosingspondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease,Crohn's disease, ulcerative colitis, uveitis, or chronic obstructivepulmonary disease. In some embodiments, the inflammatory disease,disorder or condition is associated with a protein, wherein the proteinis IL-1β, IL-2, IL-6, TNFα, CK1α, GSPT1, or ikaros, combinations of anyof the foregoing. In some embodiments, the protein is wild-type. Inother embodiments, the protein is a mutant form of the protein. In someembodiments, the protein is overexpressed.

Additional Therapeutic Agents

Some embodiments provide pharmaceutical compositions comprising acompound of Formula (I), a compound of Formula (II), or apharmaceutically acceptable salt of any of the foregoing and a secondtherapeutic agent. In some embodiments, the second therapeutic agent isan anti-inflammatory agent. In some embodiments, the second therapeuticagent is a non-steroidal anti-inflammatory agent. In some embodiments,the second therapeutic agent is an anti-cancer agent. In someembodiments, the second therapeutic agent is an immunostimulatory agent.In some embodiments, the second therapeutic agent is animmunosuppressive agent. In some embodiments, the second therapeuticagent is an antibody.

In some embodiments, the second therapeutic agent is selected fromaspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen;naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen;oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac;ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam;meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid;meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides;clonixin; licofelone; dexamethasone; and prednisone. In someembodiments, the second therapeutic agent is mechlorethamine;cyclophosphamide; melphalan; chlorambucil; ifosfamide; busulfan;N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine (CCNU);semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine;mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ);cisplatin; carboplatin; or oxaliplatin. In some embodiments, the secondtherapeutic agent is vincristine; vinblastine; vinorelbine; vindesine;vinflunine; paclitaxel; docetaxel; etoposide; teniposide; tofacitinib;ixabepilone; irinotecan; topotecan; camptothecin; doxorubicin;mitoxantrone; or teniposide. In some embodiments, the second therapeuticagent is actinomycin; bleomycin; plicamycin; mitomycin; daunorubicin;epirubicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone;cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinicacid; methotrexate; melphalan; capecitabine; mechlorethamine;uramustine; melphalan; chlorambucil; ifosfamide; bendamustine;6-mercaptopurine; or procarbazine. In some embodiments, the secondtherapeutic agent is cladribine; pemetrexed; fludarabine; gemcitabine;hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine;cytarabine; cytarabine liposomal; pralatrexate; floxuridine;fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel;tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed;pemetrexed; carmofur; or floxuridine. In some embodiments, the secondtherapeutic agent is azacitidine; decitabine; hydroxycarbamide;topotecan; irinotecan; belotecan; teniposide; aclarubicin; epirubicin;idarubicin; amrubicin; pirarubicin; valrubicin; zorubicin; mitoxantrone;pixantrone; mechlorethamine; chlorambucil; prednimustine; uramustine;estramustine; carmustine; lomustine; fotemustine; nimustine;ranimustine; carboquone; thioTEPA; triaziquone; or triethylenemelamine.In some embodiments, the second therapeutic agent is nedaplatin;satraplatin; procarbazine; dacarbazine; temozolomide; altretamine;mitobronitol; pipobroman; actinomycin; bleomycin; plicamycin;aminolevulinic acid; methyl aminolevulinate; efaproxiral; talaporfin;temoporfin; verteporfin; alvocidib; seliciclib; palbociclib; bortezomib;carfilzomib; anagrelide; masoprocol; olaparib; belinostat; panobinostat;romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone;amsacrine; trabectedin; alitretinoin; tretinoin; demecolcine;elsamitrucin; etoglucid; lonidamine; lucanthone; mitoguazone; mitotane;oblimersen; omacetaxine mepesuccinate; or eribulin. In some embodiments,the second therapeutic agent is azathioprine; mycophenolic acid;leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus;abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra;sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus;zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol;golimumab; infliximab; nerelimomab; mepolizumab; omalizumab;faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept;otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab;zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; orocrelizumab. In some embodiments, the second therapeutic agent ispascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab;aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod;ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab;natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab;inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab;maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab;siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept;belatacept; pegsunercept; aflibercept; alefacept; or rilonacept.

Dosing Regimes

In some embodiments, about 1 mg to about 5 grams, or any amount inbetween, of a compound of Formula (I), a compound of Formula (II), or apharmaceutically acceptable salt of any of the foregoing is administeredeach day, each week, or each cycle of treatment.

In some embodiments, a compound of Formula (I), a compound of Formula(II), or a pharmaceutically acceptable salt of any of the foregoing isadministered once per day, twice per day, three times per day, fourtimes per day, or more than four times per day. In some embodiments, acompound of Formula (I), a compound of Formula (II), or apharmaceutically acceptable salt of any of the foregoing is administeredonce per day, twice per day, three times per day, four times per day, ormore than four times per cycle of treatment.

In some embodiments, each cycle of treatment lasts from 1 day to 14days, or any value in between. In some embodiments, each cycle oftreatment has from at least one day up to fourteen days, or any value inbetween, between administration. In some embodiments, each cycle oftreatment includes one or more additional therapeutic agents, asdescribed herein. In some embodiments, a compound of Formula (I), acompound of Formula (II), or a pharmaceutically acceptable salt of anyof the foregoing is provided intravenously over about 10 minutes to overabout 4 h, or any value in between.

Pharmaceutical Compositions

Some embodiments provide a pharmaceutical composition, comprising acompound of Formula (I) (including Formula (Ia) and (Ib)), a compound ofFormula (II) (including Formula (II′), (IIa), (IIb) and (IIb′)), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.

One or more of the compounds of preferred embodiments can be provided inthe form of pharmaceutically acceptable salts, active metabolites, ortautomers thereof. Some embodiments can be provided in pharmaceuticalcompositions comprising a therapeutically effective amount of thecompound. In some embodiments, the pharmaceutical composition alsocontains at least one pharmaceutically acceptable inactive ingredient.The pharmaceutical composition can be formulated for intravenousinjection, subcutaneous injection, oral administration, buccaladministration, inhalation, nasal administration, topicaladministration, transdermal administration, ophthalmic administration,or otic administration. The pharmaceutical composition can be in theform of a tablet, a pill, a capsule, a liquid, an inhalant, a nasalspray solution, a suppository, a suspension, a gel, a colloid, adispersion, a solution, an emulsion, an ointment, a lotion, an eye drop,or an ear drop.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds and/or salts disclosed herein with other chemical components,such as one or more excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.Pharmaceutical compositions will generally be tailored to the specificintended route of administration.

As used herein, an “excipient” refers to essentially inert substancesthat are added to a pharmaceutical composition to provide, withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. For example,stabilizers such as anti-oxidants and metal-chelating agents areexcipients. Excipients also include ingredients in a pharmaceuticalcomposition that lack appreciable pharmacological activity but may bepharmaceutically necessary or desirable. For example, to increase thebulk of a potent drug whose mass is too small for manufacture and/oradministration. It may also be a liquid for the dissolution of a drug tobe administered by injection, ingestion or inhalation. For example, abuffered aqueous solution such as, without limitation, phosphatebuffered saline that mimics the pH and isotonicity of human blood.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orexcipients, or combinations thereof. Proper formulation is dependentupon the route of administration chosen. Techniques for formulation andadministration of the compounds described herein are known to thoseskilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound, salt and/or compositionexist in the art including, but not limited to, oral, rectal, pulmonary,topical, aerosol, injection, infusion and parenteral delivery, includingintramuscular, subcutaneous, intravenous, intramedullary injections,intrathecal, direct intraventricular, intraperitoneal, intranasal andintraocular injections. In some embodiments, a compound of Formula (I),a compound of Formula (II), or a pharmaceutically acceptable salt of anyof the foregoing, can be administered orally.

One may also administer the compound, salt and/or composition in a localrather than systemic manner, for example, via injection or implantationof the compound directly into the affected area, often in a depot orsustained release formulation. Furthermore, one may administer thecompound in a targeted drug delivery system, for example, in a liposomecoated with a tissue-specific antibody. The liposomes will be targetedto and taken up selectively by the organ. For example, intranasal orpulmonary delivery to target a respiratory disease or condition may bedesirable.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compound and/orsalt described herein formulated in a compatible pharmaceuticalexcipient may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

Other objects, features, and advantages of the compounds, methods, andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingschemes, which are not in any way intended to limit the scope of theclaims.

Characterization of the compounds disclosed herein is performed withBruker AV-500 and Bruker DRX-500 NMR spectrometers and a Perkin ElmerPE-SCIEX API-150 mass spectrometer.

Example 1 Compound 1:3-[8-Oxo-3-({3-[5-(2-{4-[(5-{[5-(tert-butyl)-1,3-oxazol-2-yl]methylthio}-1,3-thiazol-2-ylamino)carbonyl]-1-piperidyl}acetylamino)pentyl]ureido}methyl)-2-thia-7-azabicyclo[3.3.0]octa-1(5),3-dien-7-yl]-2,6-piperidinedione

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (100 mg, 0.228 mmol) in DMF (8 mL)at RT was added tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (56 mg,0.274 mmol) followed by HOBt (46.2 mg, 0.342 mmol), EDCI (66 mg, 0.342mmol) and DIEA (59 mg, 0.456 mmol). The mixture was stirred at RT for 10h then diluted with H₂O (10 mL) and extracted with EA. The combinedorganic layers were washed with H₂O (10 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified usingsilica gel eluting with DCM/MeOH (0% to 7%) to give tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(120 mg, 84% yield) as a solid. MS (ESI) m/z 625.1 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(85 mg, 0.224 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h then concentrated to give the amineTFA salt (90 mg, crude) as an oil. The amine TFA salt was dissolved inTHF (5 mL), then TEA (45.2 mg, 0.448 mmol) was added followed by4-nitrobenzyl chloroformate (54.2 mg, 0.269 mmol). The mixture wasstirred at RT for 1 h then concentrated to give 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(110 mg, crude). MS (ESI) m/z 445.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(120 mg, 0.192 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h then concentrated to give1-(2-((2-(2-aminoethoxy)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideTFA salt (120 mg, crude) as an oil. This was dissolved in THF (10 mL)and TEA (155 mg, 1.54 mmol) was added. A suspension of4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(110 mg, crude) in THF (2 mL) was added and the mixture was stirred atRT for 3 h then concentrated. The residue was purified using silica geleluting with DCM/MeOH (0% to 10%) followed by prep-HPLC using 0.1% TFAin water and 0.1% TFA in ACN with a gradient of 95% to 5% of the 0.1%TFA water to afford Compound 1 (59.2 mg, 37% yield) as a solid.

Example 2 Compound 2:3-{6-Oxo-2-[(3-{2-[2-(2-{4-[(5-{[5-(tert-butyl)-1,3-oxazol-2-yl]methylthio}-1,3-thiazol-2-ylamino)carbonyl]-1-piperidyl}acetylamino)ethoxy]ethyl}ureido)methyl]-3-thia-7-azabicyclo[3.3.0]octa-1,4-dien-7-yl}-2,6-piperidinedione

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (100 mg, 0.228 mmol) in DMF (8 mL)at RT was added tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (56 mg,0.274 mmol) followed by HOBt (46.2 mg, 0.342 mmol), EDCI (66 mg, 0.342mmol) and DIEA (59 mg, 0.456 mmol). The mixture was stirred at RT for 10h then diluted with H₂O and extracted with EA. The combined organiclayers were washed with H₂O, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The crude product was purified using silica gel elutingwith DCM/MeOH (0% to 7%) to give tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate (120 mg, 84% yield) as a solid. MS (ESI) m/z 625.1 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(85 mg, 0.224 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h and concentrated to give the amine TFAsalt (90 mg, crude) as an oil. The amine TFA salt was dissolved in THF(5 mL) and TEA (45.2 mg, 0.448 mmol) was added followed by 4-nitrobenzylchloroformate (54.2 mg, 0.269 mmol). The mixture was stirred at RT for 1h then concentrated to give the crude 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(110 mg, crude). MS (ESI) m/z 445.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(120 mg, 0.192 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h then concentrated to give1-(2-((2-(2-aminoethoxy)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideTFA salt (120 mg, crude) as an oil. This was dissolved in THF (10 mL)and TEA (155 mg, 1.54 mmol) was added. A suspension of4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(110 mg, crude) in THF (2 mL) was added, and the mixture was stirred atRT for 3 h then concentrated. The residue was purified using silica geleluting with DCM/MeOH (0% to 10%) followed by prep-HPLC using 0.1% TFAin water and 0.1% TFA in ACN with a gradient of 95% to 5% of the 0.1%TFA water to afford Compound 2 (59.2 mg, 37% yield) as a solid.

Example 3 Compound 3:3-{8-Oxo-3-[(3-{2-[2-(2-{4-[(5-{[5-(tert-butyl)-1,3-oxazol-2-yl]methylthio}-1,3-thiazol-2-ylamino)carbonyl]-1-piperidyl}acetylamino)ethoxy]ethyl}ureido)methyl]-2-thia-7-azabicyclo[3.3.0]octa-1(5),3-dien-7-yl}-2,6-piperidinedione

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(80 mg, 0.211 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h then concentrated to give3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneTFA salt (90 mg, crude) as an oil.

3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneTFA salt was dissolved in THF (5 mL) and TEA (42.6 mg, 0.422 mmol) wasadded followed by 4-nitrobenzyl chloroformate (50.9 mg, 0.253 mmol). Themixture was stirred at RT for 1 h then concentrated to give4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(94 mg, crude). MS (ESI) m/z 445.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(70 mg, 0.112 mmol) in DCM (4 mL) at RT was added TFA (1 mL). Themixture was stirred at RT for 1 h then concentrated to give1-(2-((2-(2-aminoethoxy)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideTFA salt (80 mg, crude) as an oil. 1-(2-((2-(2-Aminoethoxy)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide TFA salt was dissolved in THF (5 mL) and TEA(90 mg, 0.896 mmol) was added. A suspension of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(94 mg, crude) in THF (2 mL) was added. The mixture was stirred at RTfor 3 h then concentrated. The residue was purified using silica geleluting with DCM/MeOH (0% to 10%) followed by prep-HPLC using 0.1% TFAin water and 0.1% TFA in ACN with a gradient of 95% to 5% of the 0.1%TFA water to afford Compound 3 (7.9 mg, 8% yield) as a solid.

Example 4 Compound 4:3-[2-({3-[7-(4-{5-Chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl]-2-pyrimidinylamino}cyclohexylamino)-7-oxoheptyl]ureido}methyl)-6-oxo-3-thia-7-azabicyclo[3.3.0]octa-1,4-dien-7-yl]-2,6-piperidinedione

To a solution of(1r,4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(200 mg, 0.526 mmol) in DMF (10 mL) at RT was added7-((tert-butoxycarbonyl)amino)heptanoic acid (129 mg, 0.526 mmol)followed by HOBt (106.5 mg, 0.789 mmol), EDCI (151.5 mg, 0.789 mmol) andDIEA (136 mg, 1.052 mmol). The mixture was stirred at RT for 16 h thendiluted with H₂O (10 mL) and extracted with EA. The combined organiclayers were washed with H₂O (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified using silica geleluting with DCM/MeOH (0% to 8%) to give tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)carbamate(260 mg, 84% yield) as a solid. MS (ESI) m/z 588.1 [M+H]⁺.

To a solution of tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)carbamate(70 mg, 0.119 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). Themixture was stirred at RT for 1 h then concentrated to give7-amino-N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)heptanamideas an oil. The crude7-amino-N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)heptanamide was dissolved in THF (5 mL) and TEA (71.4 mg, 0.714 mmol)was added. A suspension of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(29.7 mg, 0.148 mmol) in THF (1 mL) was added and the mixture wasstirred at RT for 1 h then concentrated. The residue was purified usingsilica gel eluting with DCM/MeOH (0% to 10%) to afford Compound 4 (28.6mg, 30% yield) as a solid.

Example 5 Compound 5:N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-7-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)heptanamide

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(80 mg, 0.21 mmol) in DCM (8 mL) at RT was added TFA (2 mL). The mixturewas stirred at RT for 1 h then concentrated to give the TFA salt of3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(90 mg, crude) as an oil.

To a solution of the amine TFA salt in THF (5 mL) was added TEA (42.4mg, 0.42 mmol) and 4-nitrobenzyl chloroformate (51 mg, 0.253 mmol). Themixture was stirred at RT for 1 h and concentrated to give 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(93 mg, crude). MS (ESI) m/z 445.1 [M+H]⁺.

To a solution of tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)carbamate(90 mg, 0.153 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h then concentrated to give the TFA saltof7-amino-N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)heptanamideas an oil.

To a solution of the amine TFA salt in THF (5 mL) was added TEA (124 mg,1.224 mmol) and a suspension of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(93 mg, 0.21 mmol) in THF (1 mL). The mixture was stirred at RT for 3 hthen concentrated. The residue was purified using silica gel elutingwith MeOH/DCM (0% to 8%) followed by prep-HPLC using 0.1% TFA in H₂O,0.1% TFA in ACN (5%-95%) to afford Compound 5 (16.5 mg, 14% yield) as asolid.

Example 6 Compound 6:(S)—N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)-3,11-dioxo-7-oxa-2,4,10-triazadodecan-12-yl)piperidine-4-carboxamide

To a solution of (S)-tert-butyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (70 mg,0.180 mmol) in DCM (4 mL) at RT was added TFA (1 mL). The solution wasstirred at RT for 1 h. The solvent was removed and the residue was driedto give the amine TFA salt (90 mg, crude) as an oil.

The amine TFA salt was dissolved in THF (5 mL) and TEA (37 mg, 0.36mmol) was added. Then 4-nitrobenzyl chloroformate (43.6 mg, 0.217 mmol)was added. The mixture was stirred at RT for 1 h. The solvent wasremoved to give (S)-4-nitrophenyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (81.5mg, crude). MS (ESI) m/z 453.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(90 mg, 0.144 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt (80 mg, crude) as an oil.

The amine TFA salt was dissolved in THF (5 mL) and TEA (90 mg, 0.896mmol) was added. A suspension of (S)-4-nitrophenyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (81.5mg, crude) in THF (2 mL) was added. Then the mixture was stirred at RTfor 3 h. The solvent was removed and the residue was purified usingsilica gel eluting with DCM/MeOH (0% to 10%) followed by prep-HPLC aspreviously described to afford Compound 6 (16.3 mg, 14% yield) as asolid.

Example 7 Compound 7:(S)—N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)-3,11-dioxo-7-oxa-2,4,10-triazadodecan-12-yl)piperidine-4-carboxamide

To a solution of (S)-tert-butyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate (100mg, 0.258 mmol) in DCM (8 mL) at RT was added TFA (2 mL). The solutionwas stirred at RT for 1 h. The solvent was removed and the residue wasdried to give the amine TFA salt (120 mg, crude) as an oil.

The amine TFA salt was dissolved in THF (5 mL) and TEA (52 mg, 0.516mmol) was added. Then 4-nitrobenzyl chloroformate (62.3 mg, 0.31 mmol)was added. The mixture was stirred at RT for 1 h. The solvent wasremoved to give (S)-4-nitrophenyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate (120mg, crude). MS (ESI) m/z 453.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethyl)carbamate(85 mg, 0.136 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt (100 mg, crude) as an oil.

The amine TFA salt was dissolved in THF (5 mL) and TEA (110 mg, 0.896mmol) was added. Then the suspension of (S)-4-nitrophenyl((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate (120mg, crude) in THF (2 mL) was added. Then the mixture was stirred at RTfor 3 h. The solvent was removed and the residue was purified usingsilica gel eluting with DCM/MeOH (0% to 10%) to give the crude productcompound (150 mg) as an oil. It was further purified using prep-HPLC aspreviously described to afford Compound 7 (79.4 mg, 70% yield) as asolid.

Example 8

Compound 8:N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-7-((2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)amino)-2-oxoethyl)amino)heptanamide

To a solution of tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)carbamate(400 mg, 0.681 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt (300 mg, crude) as an oil.

The amine TFA salt was dissolved in N, N-dimethylamide (16 mL), andK₂CO₃ (282 mg, 2.04 mmol) was added. The suspension was cooled to 0° C.and tert-butyl bromoacetate (133 mg, 0.681 mmol) was added. Thesuspension was stirred at RT for 3 h. The mixture was diluted with H₂O(10 mL) and extracted with EA (20 mL×2). The combined organic layerswere washed with H₂O (10 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified using silica gel eluting withMeOH/DCM (0% to 9%) to give tert-butyl2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)amino)acetate(33 mg, 8% yield) as an oil. MS (ESI) m/z 602.3 [M+H]⁺.

To a solution of tert-butyl2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)amino)acetate(55 mg, 0.0913 mmol) in DCM (4 mL) at RT was added TFA (1 mL). Thesolution was stirred at RT for 10 h. The solvent was removed and theresidue was dried to give2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)amino)aceticacid (56 mg, crude) as an oil. MS (ESI) m/z 546.2 [M+H]⁺.

To a solution of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(50 mg, 0.104 mmol) in DCM (4 mL) at RT was added TFA (1 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt (45 mg, crude) as an oil.

The amine TFA salt was dissolved in DMF (5 mL) at RT and DIEA (40 mg,0.312 mmol) was added. Then2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)amino)aceticacid (56 mg, 0.104 mmol), HOBt (21 mg, 0.156 mmol) and EDCI (29.9 mg,0.156 mmol) were added. The mixture was stirred at RT for 16 h. Thesolvent was removed and the residue was purified using prep-HPLC toafford Compound 8 (25.7 mg, 27% yield) as a solid.

Example 9 Compound 9:N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-7-((2-((2-((S)-2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)amino)heptanamide

To a solution of (S)-3-(4-amino-1-oxoisoindolin-2-yl)azepane-2,7-dione(100 mg, 0.366 mmol) in THF (5 mL) at 0° C. was added 2-chloroacetylchloride (82 mg, 0.733 mmol), followed by TEA (93 mg, 0.915 mmol). Themixture was stirred at RT for 30 min. The solvent was removed and theresidue was purified using silica gel eluting with MeOH/DCM (0% to 6%)to give(S)-2-chloro-N-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)acetamide(122 mg, 96% yield) as a solid. MS (ESI) m/z 349.9 [M+H]⁺.

To a solution of tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-7-oxoheptyl)carbamate(99 mg, 0.172 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt as an oil.

The amine TFA salt was dissolved in DMA (5 mL), then K₂CO₃ (48 mg, 0.344mmol) and potassium iodide (28 mg, 0.172 mmol) were added. Then(S)-2-chloro-N-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)acetamide(60 mg, 0.172 mmol) was added and the mixture was heated at 50° C. for 4h. The solvent was removed and the residue was purified using prep-HPLCas previously described to afford Compound 9 (42.7 mg, 31% yield) as asolid.

Example 10 Compound 10:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperidine-4-carboxamide

To a suspension of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg, 1.81mmol) in 1-methyl-2-pyrrolidinone (10 mL) was added tert-butyl(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (636 mg, 2.17mmol) and DIEA (700 mg, 5.43 mmol). The mixture was heated at 100° C.under microwave irradiation for 50 min, then cooled to RT, diluted withH₂O (20 mL) and extracted with EA. The combined organic layers werewashed with H₂O, dried over Na₂SO₄, filtered and concentrated to givethe crude product which was purified using silica gel eluting with EA/PE(10% to 88%) to give tert-butyl(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate(502 mg, 55% yield) as an oil. MS (ESI) m/z 549.3 [M+1]⁺.

To a solution of tert-butyl(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate(130 mg, 0.242 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h and concentrated to give the amine TFA salt whichwas dissolved in DMF (5 mL). To the solution was added DIEA (94 mg,0.729 mmol), EDCI (70 mg, 0.365 mmol), HOBt (49 mg, 0.365 mmol) and2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (106 mg, 0.243 mmol). After 16 h at RT, the mixture was dilutedwith H₂O and extracted with EA. The combined organic layers were washedwith H₂O, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct which was purified using prep-TLC using DCM/MeOH (10:1) toafford Compound 10 (48.4 mg, 23% yield) as a solid.

Example 11 Compound 11:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)pentyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (200 mg, 0.46 mmol) in DMF (5 mL) was added tert-butyl(5-aminopentyl)carbamate (111 mg, 0.55 mmol) and DIEA (118 mg, 0.92mmol), followed by HOBt (93 mg, 0.69 mmol) and EDCI.HCl (133 mg, 0.69mmol). The mixture was stirred at RT overnight, diluted with H₂O, andextracted with EA. The combined organic layers were washed withsaturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated to givethe crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give tert-butyl(5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)carbamate(196 mg, 69% yield) as a solid. MS (ESI) m/z 623.2 [M+H]⁺.

To a solution of tert-butyl(5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)carbamate (130mg, 0.211 mmol) in DCM (6 mL) was added TFA (3 mL). The mixture wasstirred at RT for 0.5 h then concentrated to give1-(2-((5-aminopentyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideas a TFA salt. MS (ESI) m/z 523.2 [M+H]⁺.

To a solution of1-(2-((5-aminopentyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(110 mg, as TFA salt) in THF (5 mL) was added 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(94 mg, 0.211 mmol) and TEA (42 mg, 0.422 mmol) at RT. After 2 h, themixture was concentrated and purified using prep-HPLC as previouslydescribed to afford Compound 11 (5.4 mg, 3% yield) as a solid.

Example 12 Compound 12:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((3-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)propyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (200 mg, 0.46 mmol) in DMF (5 mL)was added tert-butyl (3-aminopropyl)carbamate (95 mg, 0.55 mmol) andDIEA (118 mg, 0.92 mmol), followed by HOBt (93 mg, 0.69 mmol) andEDCI.HCl (133 mg, 0.69 mmol). The mixture was stirred at RT overnight,then diluted with H₂O and extracted with EA. The combined organic layerswere washed with saturated NaHCO₃, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 10%) to give tert-butyl(3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)carbamate(185 mg, 68% yield) as a solid. MS (ESI) m/z 595.2 [M+H]⁺.

To a solution of tert-butyl(3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)carbamate(125 mg, 0.211 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT for 0.5 h then concentrated to give1-(2-((3-aminopropyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideas a TFA salt. MS (ESI) m/z 495.2 [M+H]⁺.

To a solution of1-(2-((3-aminopropyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(104 mg, as TFA salt) in THF (5 mL) was added 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(94 mg, 0.211 mmol) and TEA (42 mg, 0.422 mmol) at RT. After 2 h, themixture was concentrated to give the crude product, which was purifiedusing prep-HPLC as previously described to afford Compound 12 (31.9 mg,19% yield) as a solid.

Example 13 Compound 13:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,14-dioxo-7,10-dioxa-2,4,13-triazapentadecan-15-yl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (250 mg, 0.57 mmol) in DMF (2 mL)at RT was added tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate(156 mg, 0.62 mmol), HOBT (116 mg, 0.85 mmol), EDCI (164 mg, 0.85 mmol)and DIEA (148 mg, 1.48 mmol). The mixture was stirred at RT for 4 h thenconcentrated and purified using silica gel eluting with DCM/MeOH (50:1to 20:1) to give tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(350 mg, 91% yield) as an oil. MS (ESI) m/z 669.3 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(147 mg, 0.220 mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). After 1h, the mixture was concentrated and the residue was dissolved in THF (5mL). TEA (177 mg, 1.76 mmol) and 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(160 mg, 0.264 mmol) were added at RT. After 3 h, the mixture wasconcentrated and purified using prep-HPLC to afford Compound 13 (36.7mg, 19% yield) as a solid.

Example 14 Compound 14:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of 2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (500 mg, 1.14 mmol) inDMF (10 mL) was added tert-butyl (4-aminobutyl) carbamate (258 mg, 1.37mmol) and DIEA (294 mg, 2.28 mmol), followed by2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 650 mg, 1.70 mmol). After 1 h, the mixturewas diluted with H₂O and extracted with EA. The combined organic layerswere washed with saturated NaHCO₃, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 10%) to give tert-butyl(4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)carbamate(470 mg, 81% yield) as a solid. MS (ESI) m/z 609.2 [M+H]⁺.

To a solution of tert-butyl(4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)carbamate (470 mg,0.773 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirredat RT for 0.5 h. The solvent was removed and the residue was dried togive the amine TFA salt. MS (ESI) m/z 509.2 [M+H]⁺.

To a solution of1-(2-((5-aminopentyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(392 mg, as the TFA salt) in DMF (20 mL) was added tert-butyl2-bromoacetate (150 mg, 0.77 mmol) and K₂CO₃ (106 mg, 0.77 mmol) at RT.After 16 h, the mixture was diluted with H₂O and extracted with EA. Thecombined organic layers were washed with saturated NaHCO₃, dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givetert-butyl 2-((4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)amino)acetate(120 mg, 25% yield) as a solid. MS (ESI) m/z 623.2 [M+H]⁺.

To a solution of tert-butyl2-((4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)amino)acetate(120 mg, 0.193 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 16 h. The solvent was removed and the residue wasdried to give 2-((4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)amino)aceticacid (120 mg crude). MS (ESI) m/z 509.2 [M+H]⁺.

To a solution of 2-((4-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)butyl)amino)aceticacid (120 mg crude, 0.193 mmol) in DMF (10 mL) was added3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(71 mg, 0.254 mmol) and TEA (64 mg, 0.636 mmol), followed bypropanephosphonicacidanhydride (T₃P, 135 mg, 0.424 mmol). After 2 h, themixture was diluted with H₂O and extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified usingprep-TLC using DCM/MeOH (20:1) to afford Compound 14 (20 mg, 12% yield)as a solid.

Example 15 Compound 15:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-7-methyl-3,11-dioxo-2,4,7,10-tetraazadodecan-12-yl)piperidine-4-carboxamide

To a solution of N¹-(2-aminoethyl)-N¹-methylethane-1,2-diamine (1.1 g,9.4 mmol) in DCM (24 mL) at 0° C. was slowly added (Boc)₂O (614 mg, 2.8mmol in 4 mL DCM). The mixture was stirred at 0° C. for 1 h then warmedto RT. After 2 h, the mixture was diluted with DCM and washed withbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to give tert-butyl(2-((2-aminoethyl)(methyl)amino)ethyl)carbamate (600 mg, 30% yield) asan oil.

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (250 mg, 0.57 mmol) in DMF (2 mL) at RT was added tert-butyl(2-((2-aminoethyl)(methyl)amino)ethyl) carbamate (161 mg, 0.74 mmol),HOBT (116 mg, 0.85 mmol), EDCI (164 mg, 0.85 mmol) and DIEA (148 mg,1.48 mmol). The mixture was stirred at RT for 5 h then concentrated. Theresidue was purified using silica gel eluting with DCM/MeOH (50:1 to20:1) to give tert-butyl(2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)carbamate(210 mg, 57% yield) as a solid. MS (ESI) m/z 638.3 [M+H]⁺.

To a solution of tert-butyl(2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)carbamate(150 mg, 0.235 mmol) in DCM (4 mL) at RT was added TFA (1 mL). After 1h, the mixture was concentrated to give the amine TFA salt (6 mL).

To a solution of the amine TFA salt in THF was added TEA (190 mg, 1.88mmol) and4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(140 mg, 0.237 mmol) at RT. The mixture was stirred for 4 h andconcentrated to give the crude product, which was purified usingprep-HPLC as previously described to afford Compound 15 (6.5 mg, 3%yield) as a solid.

Example 16 Compound 16:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)acetamide

To a solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(200 mg, 0.504 mmol) in DMF (8 mL) at RT was added K₂CO₃ (208 mg, 1.51mmol) followed by tert-butyl 2-bromoacetate (100 mg, 0.504 mmol). Themixture was stirred at RT for 5 h, then diluted with H₂O and extractedwith EA. The combined organic layers were washed with H₂O, dried overNa₂SO₄, filtered and concentrated to give the crude product which waspurified using prep-TLC eluting with DCM/MeOH (15:1) to give tert-butyl2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetate(139 mg, 58% yield) as an oil. MS (ESI) m/z 475.2 [M+H]⁺.

To a solution of tert-butyl2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetate(139 mg, 0.293 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdried to give2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (123 mg, crude) as the TFA salt. MS (ESI) m/z 419.2 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(130 mg, 0.343 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Thesolution was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt (120 mg, crude) as an oil.

To a solution of the amine TFA salt in THF (5 mL) was added TEA (87 mg,0.858 mmol) and 4-nitrobenzyl chloroformate (104 mg, 0.515 mmol). Themixture was stirred at RT for 2 h. The solvent was removed to afford4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(153 mg, crude). MS (ESI) m/z 445.1 [M+H]⁺.

To a solution of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(153 mg, 0.343 mmol) in THF (5 mL) at 0° C. was added TEA (173 mg, 1.72mmol) followed by tert-butyl (5-aminopentyl)carbamate (69 mg, 0.343mmol). After 1 h, the mixture was concentrated and the residue waspurified using silica gel eluting with MeOH/DCM (0% to 8%) to give thecrude product (150 mg) which was dissolved in DCM and washed with H₂O,dried over Na₂SO₄, filtered and concentrated to give tert-butyl(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)carbamate(61 mg, 35% yield) as an oil. MS (ESI) m/z 408.2 [M-Boc+H]⁺.

To a solution of tert-butyl(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)carbamate(61 mg, 0.12 mmol) in DCM (8 mL) was added TFA (2 mL). After 1 h, themixture was concentrated to give the amine TFA salt which was dissolvedin DMF (5 mL). DIEA (47 mg, 0.36 mmol),2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (56 mg, 0.12 mmol), HOBt (24 mg, 0.18 mmol) and EDCI.HCl (35 mg,0.18 mmol) were added. The mixture was stirred at RT overnight. Thesolvent was removed and the residue was purified using prep-HPLC aspreviously described to afford Compound 16 (17.6 mg, 18% yield) as asolid.

Example 17 Compound 17:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)acetamide

To a solution of tert-butyl(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)carbamate(53 mg, 0.105 mmol) in DCM (4 mL) was added TFA (1 mL). After 1 h, themixture was concentrated to give the amine TFA salt which was dissolvedin DMF (5 mL). DIEA (40 mg, 0.315 mmol),((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)glycine(see experimental for Compound 25), 42 mg, 0.105 mmol), HOBt (22 mg,0.158 mmol) and EDCI.HCl (31 mg, 0.158 mmol) were added. The mixture wasstirred at RT overnight. The solvent was removed and the residue waspurified using prep-HPLC as previously described to afford Compound 17(13.3 mg, 16% yield) as a solid.

Example 18 Compound 18:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((7-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)heptyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (200 mg, 0.46 mmol) in DMF (5 mL) was added tert-butyl(7-aminoheptyl)carbamate (126 mg, 0.55 mmol) and DIEA (118 mg, 0.92mmol), followed by HOBt (93 mg, 0.69 mmol) and EDCI.HCl (133 mg, 0.69mmol). After overnight at RT, the mixture was diluted with H₂O andextracted with EA. The combined organic layers were washed withsaturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated to givethe crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give tert-butyl(7-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)heptyl)carbamate(243 mg, 82% yield) as a solid. MS (ESI) m/z 651.2 [M+H]⁺.

To a solution of tert-butyl(7-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)heptyl)carbamate (186mg, 0.286 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture wasstirred at RT for 0.5 h. After removing the solvent, the crude amine wasused for the next step directly as the TFA salt. MS (ESI) m/z 551.2[M+H]⁺.

To a solution of1-(2-((7-aminoheptyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(116 mg, as TFA salt) in THF (5 mL) was added 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(94 mg, 0.211 mmol) and TEA (42 mg, 0.422 mmol) at RT. The solution wasstirred for 2 h then concentrated to give the crude product, which waspurified using prep-HPLC as previously described to afford Compound 18(6.2 mg, 3% yield) as a solid.

Example 19 Compound 19:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)piperidine-4-carboxamide

To a solution ofN-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide (100 mg, 026 mmol) in DMF (6 mL) at RT wasadded tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (81.8 mg,0.26 mmol) and K₂CO₃ (71.8 mg, 0.52 mmol). The mixture was stirred at RTovernight then the mixture was diluted with water and extracted withDCM. The organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified using silica gel eluting with MeOH/DCM (0% to10%) to give tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)ethoxy)ethoxy)ethyl)carbamate(121 mg, 75% yield) as a solid. MS (ESI) m/z 612.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)ethoxy)ethoxy)ethyl)carbamate (121mg, 0.198 mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. The solutionwas then stirred at RT for 2 h and concentrated to give the TFA salt of1-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl) thio)thiazol-2-yl)piperidine-4-carboxamide (100 mgcrude) as an oil. MS (ESI) m/z 512.0 [M+H]⁺.

To a solution of1-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(100 mg, as the TFA salt) in THF (5 mL) was added 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamateand TEA (52.6 mg, 0.526 mmol) at RT. The solution was stirred for 2 hand concentrated to give the crude product, which was purified usingprep-HPLC as previously described to afford Compound 19 (39.4 mg, 18%yield) as a solid.

Example 20 Compound 20:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(8-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)octyl)piperidine-4-carboxamide

To a solution ofN-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide (100 mg, 0.263 mmol) in DMF (5 mL) was addedtert-butyl (8-iodooctyl)carbamate (93 mg, 0.263 mmol) and K₂CO₃ (73 mg,0.526 mmol). The mixture was diluted with H₂O and extracted with EA. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified using prep-HPLC as previouslydescribed to give tert-butyl(8-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)octyl)carbamate(136 mg, 86% yield) as an oil. MS (ESI) m/z 608.2 [M+H]⁺.

To a solution of tert-butyl(8-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)octyl)carbamate (128 mg, 0.211mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. The solution wasstirred at RT for 2 h. The solvent was removed to give1-(8-aminooctyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(107 mg, as the TFA salt) as an oil. MS (ESI) m/z 508.2 [M+H]⁺.

To a solution of 1-(8-aminooctyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide (107 mg, as TFA salt)in THF (5 mL) was added4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamateand TEA (42 mg, 0.211 mmol) at RT. The mixture was stirred for 2 h thenconcentrated to give the crude product which was purified usingprep-HPLC as previously described to afford Compound 20 (37.3 mg, 22%yield) as a solid.

Example 21 Compound 21:1-(6-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of(1r,4r)-N¹-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine(600 mg, 1.44 mmol) in DMF (15 mL) at RT was added K₂CO₃ (497 mg, 3.6mmol), followed by tert-butyl (6-bromohexyl)carbamate (403 mg, 1.44mmol). The mixture was stirred at 70° C. for 7 h, then diluted with H₂O(10 mL) and extracted with EA (30 mL×2). The combined organic layerswere washed with H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 10%) to give tert-butyl(6-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate(259 mg, 33% yield) as an oil. MS (ESI) m/z 544.4 [M+H]⁺.

To a solution of tert-butyl(6-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate(259 mg, 0.477 mmol) in THF/H₂O (15 mL/4.5 mL) at 0° C. was added sodiumcarbonate (76 mg, 0.716 mmol), followed by Cbz-Cl (203 mg, 1.19 mmol).The mixture was stirred at RT overnight, then diluted with H₂O (10 mL)and extracted with EA (15 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified using silica gel eluting with MeOH/DCM (0% to 5% to givebenzyl(6-((tert-butoxycarbonyl)amino)hexyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(288 mg, 89% yield) as an oil. MS (ESI) m/z 678.4 [M+H]⁺.

To a solution of benzyl (6-((tert-butoxycarbonyl)amino)hexyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(89 mg, 0.132 mmol) in DCM (4 mL) at 0° C. was added TFA (1 mL). Themixture was stirred at RT for 1 h then concentrated. The resulting amineTFA salt was dissolved in THF (5 mL) and TEA (41 mg, 0.396 mmol) wasadded. The mixture was stirred at 0° C. for 5 min. Then the suspensionof 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(117 mg, crude) in THF (1 mL) was added. The mixture was stirred at RTfor 1 h, then diluted with H₂O (10 mL) and extracted with DCM (15 mL×2).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with EA in PE from 10% to 50% to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(6-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)hexyl)carbamate(44 mg, 38% yield) as a solid.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(6-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)hexyl)carbamate(48 mg, 0.057 mmol) in AcOH (1.5 mL) at RT was added HBr (33% in AcOH,1.5 mL). The mixture was stirred at RT for 10 min. The solvent wasremoved and the residue was dried to give the crude product which wasdissolved in DMF (2 mL) and adjusted to pH about 7 with TEA. The solventwas removed and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 21 (21.2 mg, 50% yield) as a solid.

Example 22 Compound 22:1-(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(360 mg, 0.56 mmol) in DMF (10 mL) was added tert-butyl(8-bromooctyl)carbamate (188 mg, 0.611 mmol) and K₂CO₃ (191 mg, 1.39mmol). The mixture was stirred at 70° C. for 16 h. The mixture wasdiluted with H₂O (10 mL) and extracted with DCM (15 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 10%) to give tert-butyl(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(200 mg, 61% yield) as a solid. MS (ESI) m/z 588.2 [M+H]⁺.

To a solution of tert-butyl(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(180 mg, 0.31 mmol) in THF (10 mL) and water (3 mL) was added Benzylchloroformate (157 mg, 0.92 mml) and Na₂CO₃ (93.2 mg, 0.92 mml). Themixture was stirred at RT for 16 h, then diluted with H₂O (10 mL) andextracted with DCM (15 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified using silica gel eluting with MeOH/DCM(0% to 10%) to give benzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(210 mg, 85% yield) as an oil. MS (ESI) m/z 694.2 [M+H]⁺.

To a solution of benzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(190 mg, 0.264 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). After 2h, the mixture was concentrated to give the amine TFA salt (200 mg,crude) as an oil.

To a solution of the amine TFA salt in THF (10 mL) was added TEA (67 mg,0.66 mmol) and 4-nitrobenzyl chloroformate (80 mg, 0.396 mmol). Themixture was stirred at RT for 16 h. The solvent was removed to givebenzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(((4-nitrophenoxy)carbonyl)amino)octyl)carbamate(229 mg, crude). MS (ESI) m/z 759.1 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(92 mg, 0.24 mmol) in DCM (4 mL) was added TFA (1 mL). After 2 h, themixture was concentrated to give the amine TFA salt.

To a solution of the amine TFA salt in THF (5 mL).was added TEA (49 mg,0.484 mmol) and benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(((4-nitrophenoxy)carbonyl)amino)octyl)carbamate(190 mg, 0.242 mmol). The mixture was stirred at RT for 16 h. Thesolvent was removed and the residue was purified using silica geleluting with MeOH/DCM (0% to 10%) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)octyl)carbamate(40 mg, 18% yield) as a solid. MS (ESI) m/z 927.2 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)octyl)carbamate(40 mg, 0.043 mmol) in AcOH (1.5 mL) was added HBr (1.5 mL, 33% inAcOH). The mixture was stirred at RT for 2 h then diluted with H₂O andTEA and extracted with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified using prep-HPLC as previously described toafford Compound 22 (7.5 mg, 22% yield) as a solid.

Example 23 Compound 23:1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of(1r,4r)-N¹-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine(500 mg, 1.20 mmol) in DMF (10 mL) was added K₂CO₃ (414 mg, 3.00 mmol),followed by tert-butyl (8-bromooctyl)carbamate (336 mg, 1.09 mmol). Themixture was stirred at 70° C. overnight. The mixture was diluted withH₂O and extracted with DCM. The combined organic layers were washed withH₂O, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified using silica gel eluting with MeOH/DCM (0%to 10%) to give tert-butyl(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(198 mg, 29% yield) as an oil. MS (ESI) m/z 571.7 [M+H]⁺.

To a solution of tert-butyl(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(198 mg, 0.35 mmol) in THF/H₂O (12 mL/3.6 mL) at RT was added sodiumcarbonate (112 mg, 1.05 mmol), followed by benzyl chloroformate (298 mg,1.75 mmol). The mixture was stirred at RT overnight, diluted with H₂O,and extracted with EA. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givebenzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(100 mg, 41% yield) as an oil. MS (ESI) m/z 705.9 [M+H]⁺.

To a solution of benzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(100 mg, 0.142 mmol) in DCM (4 mL) at 0° C. was added TFA (1 mL). After1 h at RT, the mixture was concentrated to give the amine TFA salt,which was dissolved in THF (5 mL).

To the solution of amine TFA salt in THF was added TEA (43 mg, 0.426mmol) and 4-nitrobenzyl chloroformate (57.2 mg, 0.284 mmol). The mixturewas stirred at RT for 1 h. The solvent was removed to give the crudeproduct, which was purified using silica gel eluting with EA/PE (0% to50%) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(8-(((4-nitrophenoxy)carbonyl)amino)octyl)carbamate(84 mg, 77% yield) as an oil. MS (ESI) m/z 770.8 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(8-(((4-nitrophenoxy)carbonyl)amino)octyl)carbamate(84 mg, 0.109 mmol) in THF (5 mL) at RT was added3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(30.4 mg, 0.109 mmol) and TEA (34 mg, 0.327 mmol). The mixture wasstirred at 40° C. for 2 h. The solvent was removed and the residue waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givebenzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(8-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)octyl)carbamate(45 mg) as a solid. MS (ESI) m/z 911.1 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(8-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)octyl)carbamate(45 mg, 0.049 mmol) in AcOH (1.5 mL) at RT was added HBr (33% in AcOH,1.5 mL). The mixture was stirred at RT for 30 min. Upon removal ofsolvent, the residue was dissolved in DMF (2 mL). After adjusting to pHabout 7 with TEA, the mixture was concentrated and the residue waspurified using prep-HPLC as previously described to afford Compound 23(10 mg, 26% yield) as a solid.

Example 24 Compound 24:1-(6-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(220 mg, 0.611 mmol) in DMF (8 mL) was added tert-butyl(6-bromohexyl)carbamate (188 mg, 0.672 mmol) and K₂CO₃ (169 mg, 1.22mmol). The mixture was stirred at 70° C. for 16 h then diluted with H₂Oand extracted with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givetert-butyl(6-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate(150 mg, 44% yield) as a solid. MS (ESI) m/z 560.2 [M+H]⁺.

To a solution of tert-butyl(6-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate(150 mg, 0.268 mmol) in THF (4 mL) and water (1 mL) was added benzylchloroformate (137 mg, 0.805 mml) and Na₂CO₃ (85 mg, 0.805 mml). Themixture was stirred at RT for 16 h then diluted with H₂O and extractedwith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givebenzyl(6-((tert-butoxycarbonyl)amino)hexyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(160 mg, 86% yield) as an oil. MS (ESI) m/z 694.2 [M+H]⁺.

To a solution of benzyl(6-((tert-butoxycarbonyl)amino)hexyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(150 mg, 0.216 mmol) in DCM (4 mL) at RT was added TFA (1 mL). After 1h, the mixture was concentrated to give the amine TFA salt (130 mg,crude) as an oil, which was dissolved in THF (4 mL). TEA (55 mg, 0.54mmol) and 4-nitrobenzyl chloroformate (65 mg, 0.324 mmol) were added.The mixture was stirred at RT for 16 h. The solvent was removed to givebenzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(6-(((4-nitrophenoxy)carbonyl)amino)hexyl)carbamate(163.7 mg, crude). MS (ESI) m/z 759.1 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(58 mg, 0.15 mmol) in DCM (4 mL) was added TFA (1 mL). After 2 h at RT,the mixture was concentrated to give the amine TFA salt, which wasdissolved in THF (4 mL). TEA (51 mg, 0.508 mmol) and benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(6-(((4-nitrophenoxy)carbonyl)amino)hexyl)carbamate(77 mg, 0.101 mmol) were added. The mixture was stirred at RT for 16 h.The solvent was removed to give the crude compound which was purifiedusing silica gel eluting with MeOH/DCM (0% to 10%) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(6-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)hexyl)carbamate(55 mg, 60% yield) as a solid. MS (ESI) m/z 899.2 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(6-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)hexyl)carbamate(55 mg, 0.061 mmol) in AcOH (1.5 mL) was added HBr (1.5 mL, 33% inAcOH). The mixture was stirred at RT for 2 h then diluted with H₂O (10ml). TEA (1 mL) was added and the mixture was extracted with DCM. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedusing prep-HPLC as previously described to afford Compound 24 (18 mg,39% yield) as a solid.

Example 25 Compound 25:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide

To a solution of(1r,4r)-N¹-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine(1.0 g, 2.4 mmol) in DMF (10 mL) at RT was added K₂CO₃ (994 mg, 7.2mmol), followed by tert-butyl 2-bromoacetate (468 mg, 2.4 mmol). Themixture was stirred at RT for 7 h, diluted with H₂O and extracted withEA. The combined organic layers were washed with H₂O, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedusing silica gel eluting with MeOH/DCM (0% to 10%) to give tert-butyl2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetate(832 mg, 77% yield) as an oil. MS (ESI) m/z 459.3 [M+H]⁺.

To a solution of tert-butyl2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetate(832 mg, 1.82 mmol) in DCM (16 mL) was added TFA (4 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdissolved in tert-butyl methyl ether (10 mL). The suspension was stirredat RT for 30 min. The suspension was filtered and the filter cake wasdried to give2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (1.08 g, crude) as the TFA salt. MS (ESI) m/z 403.2 [M+H]⁺.

To a solution of2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (300 mg, 0.466 mmol, as TFA salt) in DMF (10 mL) was added DIEA(178 mg, 1.38 mmol), followed by tert-butyl (5-aminopentyl)carbamate(113 mg, 0.559 mmol), HOBt (94 mg, 0.699 mmol) and EDCI.HCl (134 mg,0.699 mmol). The mixture was stirred at RT overnight, diluted with H₂Oand extracted with EA. The combined organic layers were washed with H₂O,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 10%) togive tert-butyl(5-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)pentyl)carbamate(201 mg, 74% yield) as an oil. MS (ESI) m/z 587.4 [M+H]⁺.

To a solution of tert-butyl(5-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)pentyl)carbamate(195 mg, 0.333 mmol) in THF/H₂O (12.5 mL/5 mL) at 0° C. was added sodiumcarbonate (106 mg, 0.999 mmol), followed by benzyl chloroformate (113mg, 0.666 mmol). The mixture was stirred at RT for 30 min, diluted withH₂O and extracted with EA. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with MeOH/DCM (0% to 6%) to givebenzyl(2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(237 mg, 99% yield) as a solid. MS (ESI) m/z 721.4 [M+H]⁺.

To a solution of benzyl(2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(181 mg, 0.251 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (7 mL) and cooled to 0° C., then K₂CO₃ (87 mg,0.628 mmol) was added, followed by tert-butyl bromoacetate (49 mg, 0.251mmol). The mixture was stirred at RT for 6 h, diluted with H₂O andextracted with DCM. The organic layer was concentrated to give the crudeproduct, which was purified using prep-TLC eluting with DCM/MeOH (10:1)to give tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oate(30 mg, 16% yield) as an oil. MS (ESI) m/z 735.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oate(30 mg, 0.041 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight then concentrated to give4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oicacid (30 mg, crude) as a TFA salt. MS (ESI) m/z 679.4 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(38 mg, 0.1 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 1 h then concentrated to give the amine TFA salt. DMF(5 mL) and DIEA (32 mg, 0.249 mmol) were added. Then4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oicacid (56 mg, 0.083 mmol), HOBt (17 mg, 0.124 mmol) and EDCI.HCl (24 mg,0.124 mmol) were added. The mixture was stirred at RT overnight. Thesolvent was removed and the residue was purified using prep-TLC elutingwith DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(65 mg, 83% yield) as a solid.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(65 mg, 0.069 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h then concentrated. The residue wasdissolved in DMF (2 mL), adjusted to a pH of about 7 with TEA, thenconcentrated. The residue was purified using prep-HPLC as previouslydescribed to afford Compound 25 (10.1 mg, 18% yield) as a solid.

Example 26 Compound 26:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3,15-dioxo-8,11-dioxa-2,5,14-triazahexadecan-16-yl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (510 mg, 1.16 mmol) in DMF (5 mL) was added tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (347 mg, 1.39 mmol) and DIEA(300 mg, 2.32 mmol), followed by HOBt (236 mg, 1.75 mmol) and EDCI.HCl(336 mg, 1.75 mmol). The mixture was stirred at RT for 12 h then dilutedwith H₂O and extracted with EA. The combined organic layers were washedwith saturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified using silica gel eluting withDCM/MeOH (0% to 10%) to give tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 68% yield) as a solid. MS (ESI) m/z 669.2 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 0.779 mmol) in DCM (10 mL) was added TFA (4 mL). The mixturewas stirred at RT for 1 h then concentrated to give the amine TFA salt,which was dissolved in DMF (8 mL) and cooled to 0° C. K₂CO₃ (322 mg,2.337 mmol) was added followed by tert-butyl bromoacetate (152 mg, 0.779mmol). The mixture was stirred at RT for 3 h then diluted with H₂O andextracted with DCM. The organic layer was concentrated and the residuewas purified using prep-TLC eluting with DCM/MeOH (10:1) to givetert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(117 mg, 22% yield) as an oil. MS (ESI) m/z 683.2 [M+H]⁺.

To a solution oftert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(117 mg, 0.171 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT for 4 h then concentrated. The residue was dissolved inDMF (8 mL) and DIEA (44 mg, 0.342 mmol) was added. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(57 mg, 0.205 mmol), HOBt (35 mg, 0.257 mmol) and EDCI.HCl (49 mg, 0.257mmol) were added. The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 26 (25.3 mg, 17% yield) as a solid.

Example 27 Compound 27:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((5-(3-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (510 mg, 1.16 mmol) in DMF (5 mL) was added tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (347 mg, 1.39 mmol) and DIEA(300 mg, 2.32 mmol), followed by HOBt (236 mg, 1.75 mmol) and EDCI.HCl(336 mg, 1.75 mmol). The mixture was stirred at RT for 12 h. The mixturewas diluted with H₂O and extracted with EA. The combined organic layerswere washed with saturated NaHCO₃, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with DCM/MeOH (0% to 10%) to give tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 68% yield) as a solid. MS (ESI) m/z 669.2 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 0.779 mmol) in DCM (10 mL) was added TFA (4 mL). The mixturewas stirred at RT for 1 h then concentrated to give the amine TFA saltwhich was dissolved in DMF (8 mL) and cooled to 0° C. K₂CO₃ (322 mg,2.337 mmol) was added, followed by tert-butyl bromoacetate (152 mg,0.779 mmol). The mixture was stirred at RT for 3 h then diluted with H₂Oand extracted with DCM. The organic layer was concentrated and theresidue was purified using prep-TLC eluting with DCM/MeOH (10:1) to givetert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(117 mg, 22% yield) as an oil. MS (ESI) m/z 683.2 [M+H]⁺.

To a solution oftert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(117 mg, 0.171 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT for 4 h then concentrated. The residue was dissolved inDMF (8 mL) and DIEA (44 mg, 0.342 mmol) was added. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(57 mg, 0.205 mmol), HOBt (35 mg, 0.257 mmol) and EDCI.HCl (49 mg, 0.257mmol) were added. The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 27 (25.3 mg, 17% yield) as a solid.

Example 28 Compound 28:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(2-(2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)amino)-2-oxoethoxy)ethoxy)ethyl)acetamide

To a solution of methyl 3-hydroxy-2-methylbenzoate (10.0 g, 0.06 mol) inDMF (50 mL) was added imidazole. The mixture was stirred at RT for 5 h.The mixture was filtered and the filtrate was concentrated. The residuewas purified using silica gel eluting with PE/EA (10:1) to give methyl3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (17.5 g, crude) as anoil.

To a solution of methyl3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (9.0 g, 32.1 mmol) inCCl₄ (30 mL) was added NBS (6.2 g, 35.0 mmol) and azodiisobutyronitrile(1.0 g, 6.4 mmol). The mixture was stirred at 70° C. for 18 h thendiluted with water. The organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified using silica gel eluting withPE/EA (10:1) to give methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate (11.7 g crude)as an oil.

To a solution of methyl2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate (2.0 g, 5.587mmol) in DMF (20 mL) was added tert-butyl 4,5-diamino-5-oxopentanoate(1.24 g, 6.145 mmol) and trimethylamine (1.4 g, 13.97 mmol). The mixturewas stirred at RT for 16 h. Tetrabutylammonium fluoride (0.88 g, 3.35mmol) was added dropwise then the mixture was stirred at 60° C. for 2 h.The mixture was diluted with sat. NaHCO₃ and extracted with EA. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified using silica gel eluting with PE/EA (1:1) to givetert-butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.82 g, 98% yield) as a solid. MS (ESI) m/z 335.1 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (900 mg, 2.69mmol) in DMF (8 mL) was added 4-(bromomethyl)benzonitrile (581 mg, 2.96mmol) and K₂CO₃ (742 mg, 5.38 mml). The mixture was stirred at RT for 16h. The mixture was diluted with water and extracted with EA. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified using silica gel eluting with PE/EA (1:1) to give tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 83% yield) as a solid. MS (ESI) m/z 450.1 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(4-((4-cyanobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 2.23 mmol) in THF (20 mL) was added Raney Ni (100 mg) anddi-tert-butyl dicarbonate (730 mg, 3.34 mmol). The mixture was degassedand purged with H₂. After 16 h at RT, the mixture was filtered and thefiltrate was concentrated. The residue was purified using silica geleluting with PE/EA (1:1) to give tert-butyl5-amino-4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.08 g, 88% yield) as a solid. MS (ESI) m/z 554.2 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.08 g, 1.95 mmol) inDCM (8 mL) was added TFA (2 mL). The mixture was stirred at RT for 2 hthen concentrated to give5-amino-4-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (0.775 mg, quant.) as a solid. MS (ESI) m/z 398.0 [M+H]⁺.

To a solution of5-amino-4-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (775 mg, 1.85 mmol) and trimethylamine (591 mg, 5.85 mmol) in THF(15 mL) was added di-tert-butyl dicarbonate (638 mg, 2.93 mmol). Themixture was stirred at RT for 3 h then concentrated to give5-amino-4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid (950 mg, quant.) as an oil. MS (ESI) m/z 498.1 [M+H]⁺.

To a solution of 5-amino-4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid (900 mg, 1.8 mmol)in CAN (25 mL) was added CDI (1.17 g, 7.2 mmol). After 16 h at 100° C.,the mixture was filtered and the filtrate was concentrated. The residuewas purified using silica gel eluting with PE/EA (1:1) to givetert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(710 mg, 74% yield) as a solid. MS (ESI) m/z 480.2 [M+H]⁺.

To a solution of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylcarbamate(110 mg, 0.229 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 2 h and concentrated to give the TFA salt of3-(4-((4-(aminomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionewhich was dissolved in DMF (5 mL).2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oic acid (76 mg,0.2756 mmol), HATU (174 mg, 0.4592 mmol) and DIEA (89 mg, 0.688 mmol)were added. After 16 h at RT, the mixture was concentrated. The residuewas purified using silica gel eluting with DCM/MeOH (10:1) to givetert-butyl(2-(2-(2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(130 mg, 90% yield) as a solid. MS (ESI) m/z 625.2 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate(100 mg, 0.16 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 2 h then concentrated to give the amine TFA salt whichwas dissolved in DMF (4 mL).2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (67 mg, 0.16 mmol), T3P (153 mg, 0.48 mmol) and TEA (48 mg, 0.48mmol) were added. The mixture was stirred at RT for 16 h thenconcentrated, and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to afford Compound 28 (34.1 mg, yield 23% yield) as asolid.

Example 29 Compound 29:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (350 mg, 0.678 mmol) in DMF (4 mL) was added DIEA (262 mg, 2.03mmol), followed by tert-butyl (4-aminobutyl)carbamate (153 mg, 0.814mmol), HOBt (137 mg, 1.02 mmol) and EDCI.HCl (195 mg, 1.02 mmol). Themixture was stirred at RT overnight, diluted with H₂O and extracted withEA. The combined organic layers were washed with H₂O, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedusing silica gel eluting with MeOH/DCM (0% to 10%) to give tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 71% yield) as a solid. MS (ESI) m/z 573.1 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 0.42 mmol) in THF/H₂O (4 mL:1 mL) at 0° C. was added sodiumcarbonate (133 mg, 1.26 mmol), followed by benzyl chloroformate (108 mg,0.63 mmol). The mixture was stirred at RT for 2 h. The mixture wasdiluted with H₂O and extracted with EA. The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 6%) togive benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 100% yield) as a solid. MS (ESI) m/z 707.1 [M+H]⁺.

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 0.425 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (4 mL) and cooled to 0° C., then K₂CO₃ (196 mg,1.275 mmol) was added, followed by tert-butyl bromoacetate (83 mg, 0.425mmol). The mixture was stirred at RT for 16 h then diluted with H₂O andextracted with DCM. The organic layer was concentrated and the residuewas purified using silica gel eluting with MeOH/DCM (0% to 6%) to givetert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 44% yield) as solid. MS (ESI) m/z 721.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 0.188 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight then concentrated to give 4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (124.5 mg, crude) as the TFA salt. MS (ESI) m/z 665.4 [M+H]⁺.

To a solution of tert-butyl ((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno [2,3-c]pyrrol-2-yl) methyl) carbamate (30 mg, 0.08mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at RTfor 2 h then concentrated. The resulting amine TFA salt was dissolved inDMF (4 mL) then TEA (24 mg, 0.237 mmol) was added, followed by4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (52 mg, 0.153 mmol) and propanephosphonicacidanhydride (75 mg,0.458 mmol). The mixture was stirred at RT for 16 h. The solvent wasremoved and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(50 mg, 68% yield) as an oil. MS (ESI) m/z 926.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(50 mg, 0.054 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 1 h then concentrated, dissolvedin DMF (2 mL), and adjusted to a pH of about 7 with TEA. The mixture wasconcentrated and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 29 (7.3 mg, 17% yield) as a solid.

Example 30 Compound 30:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oate(60 mg, 0.08 mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). Themixture was stirred at RT overnight then concentrated and dissolved inDMF (2 mL). DIEA (51 mg, 0.24 mmol) was added followed by3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(46 mg, 0.12 mmol), HOBT (16 mg, 0.12 mmol) and EDCI.HCl (24 mg, 0.12mmol). The mixture was stirred at RT overnight then concentrated. Theresidue was purified using prep-TLC eluting with DCM/MeOH (10:1) to givethe benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(65 mg, 84% yield) as a solid. MS (ESI) m/z 478.8 [M/2+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(65 mg, 0.067 mmol) in AcOH (2 mL) at RT was added HBr (2 mL, 33% inAcOH). The mixture was stirred at RT for 1 h then concentrated,dissolved in DMF (2 mL), and adjusted to a pH of about 7 with TEA. Themixture was concentrated and the residue was purified using prep-HPLC aspreviously described to afford Compound 30 (17.8 mg, 32% yield) as asolid.

Example 31 Compound 31:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (300 mg, 0.717 mmol) in DMF (10 mL) at RT was added tert-butyl(5-aminopentyl)carbamate (159 mg, 0.788 mmol), HOBT (145 mg, 1.075mmol), EDCI.HCl (206 mg, 1.08 mmol) and DIEA (277 mg, 2.15 mmol). Themixture was stirred at RT overnight then concentrated and the residuewas purified using silica gel eluting with MeOH/DCM (0% to 5%) to givetert-butyl(5-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)pentyl)carbamate(420 mg, crude) as a solid. MS (ESI) m/z 603.4 [M+H]⁺.

To a solution of tert-butyl(5-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)pentyl)carbamate(420 mg, 0.717 mmol) in THF/H₂O (12.5 mL/5 mL) at 0° C. was added sodiumcarbonate (228 mg, 2.15 mmol), followed by benzyl chloroformate (245 mg,1.434 mmol). The mixture was stirred at RT for 2 h, diluted with H₂O andextracted with EA. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedusing silica gel eluting with MeOH/DCM (0% to 6%) to give benzyl(2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(190 mg, 36% yield) as a solid. MS (ESI) m/z 737.4 [M+H]⁺.

To a solution of benzyl(2-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(190 mg, 0.258 mmol) in DCM (4 mL) at RT was added TFA (1 mL). Themixture was stirred at RT for 30 min then concentrated. The resultingamine TFA salt was dissolved in DMF (7 mL) and cooled to 0° C., thenK₂CO₃ (52 mg, 0.375 mmol) was added, followed by tert-butyl bromoacetate(50 mg, 0.258 mmol). The mixture was stirred at RT for 3 h, diluted withH₂O and extracted with DCM. The organic layer was concentrated and theresidue was purified using prep-TLC eluting with DCM/MeOH (10:1) to givetert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oate(90 mg, 46%) as a solid. MS (ESI) m/z 751.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oate(50 mg, 0.06 mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). Themixture was stirred at RT overnight. The solvent was removed and theresidue was dissolved in DMF (5 mL). Then DIEA (20 mg, 0.15 mmol),3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(25 mg, 0.08 mmol), HOBT (13 mg, 0.09 mmol) and EDCI.HCl (18 mg, 0.09mmol) were added. The suspension was stirred at RT overnight andconcentrated, then the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to give to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(60 mg, 92% yield) as a solid. MS (ESI) m/z 478.8 [M/2+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(60 mg, 0.06 mmol) in AcOH (2 mL) at RT was added HBr (2 mL, 33% inAcOH). The mixture was stirred at RT for 2 h then concentrated, and theresidue was dissolved in DMF (2 mL) and adjusted to a pH of about 7 withTEA. The mixture was concentrated and the residue was purified usingprep-HPLC as previously described to afford Compound 31 (14.1 mg, 27%yield) as a solid.

Example 32 Compound 32:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(77 mg, 0.203 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 1 h. The mixture was concentrated to give the amine asthe trifluoroacetate salt. The amine was dissolved in DMF (5 mL) andDIEA (78 mg, 0.254 mmol) was added. Then4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,13-triazapentadecan-15-oicacid (115 mg, 0.169 mmol), HOBt (35 mg, 0.254 mmol) and EDCI.HCl (49 mg,0.254 mmol) was added. The mixture was stirred at RT overnight. Thesolvent was removed and the residue was purified using prep-TLC elutingwith DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(70 mg, 44% yield) as a solid.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)carbamate(70 mg, 0.075 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h. The solvent was removed and theresidue was dissolved in DMF (2 mL) and adjusted to a pH of about 7 withTEA. The mixture was concentrated and the residue was purified usingprep-HPLC as previously described to afford Compound 32 (21.3 mg, 36%yield) as a solid.

Example 33 Compound 33:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (300 mg, 0.68 mmol) in DMF (10 mL) was added tert-butyl(5-aminopentyl)carbamate (166 mg, 0.82 mmol) and DIEA (196 mg, 1.36mmol), followed by HOBt (137 mg, 1.02 mmol) and EDCI.HCl (196 mg, 1.02mmol). The mixture was stirred at RT overnight then diluted with H₂O andextracted with EA. The combined organic layers were washed withsaturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated to givethe crude product, which was purified using silica gel eluting withDCM/MeOH (0% to 10%) to givetert-butyl(5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)carbamate(409 mg, 96% yield) as a solid. MS (ESI) m/z 623.2 [M+H]⁺.

To a solution oftert-butyl(5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)carbamate(409 mg, 0.658 mmol) in DCM (10 mL) was added TFA (5 mL). The mixturewas stirred at RT for 1 h then concentrated. The resulting amine TFAsalt was dissolved in DMF (10 mL) and cooled to 0° C., then K₂CO₃ (209mg, 1.974 mmol) was added, followed by tert-butyl bromoacetate (128 mg,0.658 mmol). After 3 h, the mixture was diluted with H₂O and extractedwith DCM. The organic layer was concentrated to give the crude productwhich was purified using prep-TLC eluting with DCM/MeOH (10:1) to givetert-butyl2-((5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)amino)acetate(120 mg, 29% yield) as an oil. MS (ESI) m/z 637.2 [M+H]⁺.

To a solution of tert-butyl2-((5-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)pentyl)amino)acetate(120 mg, 0.189 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT for 4 h. The solvent was removed and the residue wasdissolved in DMF (6 mL). DIEA (48.8 mg, 0.378 mmol) was added followedby3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(53 mg, 0.189 mmol), HOBt (38.3 mg, 0.284 mmol) and EDCI.HCl (54.5 mg,0.284 mmol). The mixture was stirred at RT overnight. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 33 (12.1 mg, 8% yield) as a solid.

Example 34 Compound 34:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,15-dioxo-8,11-dioxa-2,5,14-triazahexadecan-16-yl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (510 mg, 1.16 mmol) in DMF (5 mL) was added tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (347 mg, 1.39 mmol) and DIEA(300 mg, 2.32 mmol), followed by HOBt (236 mg, 1.75 mmol) and EDCI.HCl(336 mg, 1.75 mmol). The mixture was stirred at RT for 12 h, dilutedwith H₂O and extracted with EA. The combined organic layers were washedwith saturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified using silica gel eluting withDCM/MeOH (0% to 10%) to give tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 68% yield) as a solid. MS (ESI) m/z 669.2 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(521 mg, 0.779 mmol) in DCM (10 mL) was added TFA (4 mL). The mixturewas stirred at RT for 1 h then concentrated. The resulting amine TFAsalt was dissolved in DMF (8 mL) and cooled to 0° C., then K₂CO₃ (322mg, 2.337 mmol) was added, followed by tert-butyl bromoacetate (152 mg,0.779 mmol). The mixture was stirred at RT for 3 h, diluted with H₂O,and extracted with DCM. The organic layer was concentrated and theresidue was purified using prep-TLC eluting with DCM/MeOH (10:1) to givetert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(117 mg, 22% yield) as an oil. MS (ESI) m/z 683.2 [M+H]⁺.

To a solution oftert-butyl14-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-13-oxo-6,9-dioxa-3,12-diazatetradecan-1-oate(75 mg, 0.11 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT for 4 h then concentrated. The residue was dissolved inDMF (5 mL) and DIEA (28 mg, 0.22 mmol) was added. Then3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(30.7 mg, 0.11 mmol), HOBt (23 mg, 0.17 mmol) and EDCI.HCl (33 mg, 0.17mmol) were added. The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 34 (8.1 mg, 8% yield) as a solid.

Example 35 Compound 35:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (300 mg, 0.564 mmol) in DMF (6 mL) was added DIEA (254.6 mg, 1.974mmol), followed by tert-butyl (4-aminobutyl)carbamate (148.4 mg, 0.789mmol) and HATU (321.4 mg, 0.846 mmol). The mixture was stirred at RTovernight, then diluted with H₂O and extracted with EA. The combinedorganic layers were washed with H₂O and saturated NaHCO₃, dried overNa₂SO₄, filtered and concentrated to give tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(300 mg crude). MS (ESI) m/z 589.4 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(254 mg, 0.432 mmol) in THF/H₂O (4 mL:1 mL) at RT was added sodiumcarbonate (137.4 mg, 1.296 mmol), followed by benzyl chloroformate(110.5 mg, 0.648 mmol). After 30 min at RT, the mixture was concentratedand the residue was diluted with H₂O then extracted with EA. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 6%) to give benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(277.5 mg, 89% yield) as a solid. MS (ESI) m/z 723.4 [M+H]⁺.

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(277 mg, 0.383 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 30 min then concentrated to give benzyl(2-((4-aminobutyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(230 mg, 96% yield) as the TFA salt.

To a solution of benzyl(2-((4-aminobutyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(220 mg, 0.354 mmol, as TFA salt) in DMF (8 mL) at 0° C. was added K₂CO₃(146.4 mg, 1.06 mmol), followed by tert-butyl bromoacetate (68.9 mg,0.354 mmol). The mixture was stirred at RT for 4 h, then diluted withH₂O and extracted with DCM. The organic layer was concentrated to givethe crude product which was purified using silica gel eluting withMeOH/DCM (0% to 8% to give tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(63 mg, 24% yield) as a solid. MS (ESI) m/z 737.3 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(133 mg, 0.180 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight. The solvent was removed to give the crudeproduct as residue which was used for the next step directly. Theresidue was dissolved in DMF (4 mL). Then3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(50.47 mg, 0.181 mmol, HCl salt) and DIEA (46.7 mg, 0.362 mmol) wasadded and stirred for 5 min. Then HOBt (24.4 mg, 0.181 mmol) andEDCI.HCl (34.7 mg, 0.181 mmol) was added. The mixture was stirred at RTovernight. The solvent was removed and the residue was purified usingprep-TLC eluting with DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(93 mg, 66% yield) as a solid. MS (ESI) m/z 943.2 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(93 mg, 0.098 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the crude product. It was dissolved in DMF (2mL) and adjusted to pH about 7 with TEA. The solvent was removed and theresidue was purified using prep-HPLC as previously described to affordCompound 35 (6.2 mg, 8% yield) as a solid.

Example 36 Compound 36:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetic acid (300 mg, 0.56 mmol) inN, N-dimethylamide (8 mL) at RT was added added tert-butyl(4-aminobutyl)carbamate (106 mg, 0.56 mmol), followed by HATU (319 mg,0.84 mmol) and N, N-diisopropylethylamine (217 mg, 1.68 mmol) added. Themixture was stirred at RT for 2 h, diluted with H₂O (10 mL), andextracted with EA (15 mL×2). The combined organic layers were washedwith H₂O (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl) amino)cyclohexyl)amino)acetamido)butyl)carbamate (330mg, crude) as a solid. MS (ESI) m/z 589.3 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(330 mg, 0.56 mmol) in THF/H₂O (15 mL/4.5 mL) at 0° C. was added sodiumcarbonate (178 mg, 1.68 mmol), followed by benzyl carbonochloridate (126mg, 0.84 mmol) added. The mixture was stirred at RT for overnight andthen the suspension was diluted with H₂O (10 mL), extracted with EA (15mL×2). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 5%) to give benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(342 mg, 83% yield) as a solid. MS (ESI) m/z 724.2 [M+H]⁺

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(342 mg, 0.47 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (7 mL) and cooled to 0° C., then K₂CO₃ (138 mg,2.35 mmol) was added, followed by tert-butyl bromoacetate (92 mg, 0.47mmol) added. The mixture was stirred at RT for 6 h, diluted with H₂O (5mL), and extracted with DCM (20 mL). The organic layer was concentratedto give the crude product which was purified using prep-TLC eluting withDCM/MeOH (10:1) to give tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(225 mg, 62% yield) as an oil. MS (ESI) m/z 737.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(74 mg, 0.1 mmol) in DCM (8 mL) at RT was added TFA (2 mL). The mixturewas stirred at RT for 1 h. The solvent was removed and the residue wasdried to give acid (68 mg, crude) as an oil. The oil was dissolved inDMF (4 mL) and TEA (50 mg, 0.50 mmol) was added. Then2-(aminomethyl)-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(60 mg, 0.2 mmol) and propanephosphonicacidanhydride (95 mg, 0.3 mmol)added. The mixture was stirred at RT for 2 h. The solvent was removedand the residue was purified using prep-TLC eluting with DCM/MeOH (10:1)to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(96 mg, crude) as a solid. MS (ESI) m/z 956.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(96 mg, 0.10 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL). Themixture was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the crude product which was dissolved in DMF(2 mL) and adjusted to a pH of about 7 with TEA. The solvent was removedand the residue was purified using prep-HPLC as previously described toafford Compound 36 (10.2 mg, 12% yield) as a solid.

Example 37 Compound 37:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (350 mg, 0.678 mmol) in DMF (4 mL) was added DIEA (262 mg, 2.03mmol), followed by tert-butyl (4-aminobutyl)carbamate (153 mg, 0.814mmol), HOBt (137 mg, 1.02 mmol) and EDCI.HCl (195 mg, 1.02 mmol) wasadded. The mixture was stirred at RT overnight, diluted with H₂O (10mL), and extracted with EA (15 mL×2). The combined organic layers werewashed with H₂O (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 71% yield) as a solid. MS (ESI) m/z 573.1 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 0.42 mmol) in THF/H₂O (4 mL/1 mL) at 0° C. was added sodiumcarbonate (133 mg, 1.26 mmol), followed by benzyl chloroformate (108 mg,0.63 mmol) added. The mixture was stirred at RT for 2 h, diluted withH₂O (10 mL), and extracted with EA (15 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified using silica gel eluting with MeOH/DCM(0% to 6% to give benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 100% yield) as a solid. MS (ESI) m/z 707.1 [M+H]⁺.

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 0.425 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (4 mL) and cooled to 0° C., then K₂CO₃ (196 mg,1.275 mmol) was added, followed by tert-butyl bromoacetate (83 mg, 0.425mmol). The mixture was stirred at RT for 16 h, diluted with H₂O andextracted with DCM. The organic layer was concentrated to give the crudeproduct which was purified using silica gel eluting with MeOH/DCM (0% to6%) to give tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 44% yield) as solid. MS (ESI) m/z 721.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 0.188 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdried to give 4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (124.5 mg, crude) as the TFA salt. MS (ESI) m/z 665.4 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(60 mg, 0.153 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 2 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (4 mL), then TEA (46 mg, 0.458 mmol) was added,followed by4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (101 mg, 0.153 mmol) and propanephosphonicacid anhydride (146 mg,0.458 mmol). The mixture was stirred at RT for 16 h. The solvent wasremoved and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(90 mg, 47% yield) as a solid. MS (ESI) m/z 939.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(45 mg, 0.048 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 1 h then concentrated, and theresidue was dissolved in DMF (2 mL) and adjusted to a pH of about 7 withTEA. The solvent was removed and the residue was purified usingprep-HPLC as previously described to afford Compound 37 (7.5 mg, 20%yield) as a solid.

Example 38 Compound 38:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (300 mg, 0.564 mmol) in DMF (6 mL) was added DIEA (254.6 mg, 1.974mmol), followed by tert-butyl (4-aminobutyl)carbamate (148.4 mg, 0.789mmol) and HATU (321.4 mg, 0.846 mmol). The mixture was stirred at RTovernight, then diluted with H₂O and extracted with EA. The combinedorganic layers were washed with H₂O and saturated NaHCO₃, dried overNa₂SO₄, filtered and concentrated to give tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(300 mg crude). MS (ESI) m/z 589.4 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(254 mg, 0.432 mmol) in THF/H₂O (4 mL:1 mL) at RT was added sodiumcarbonate (137.4 mg, 1.296 mmol), followed by benzyl chloroformate(110.5 mg, 0.648 mmol). After 30 min at RT, the mixture was concentratedand the residue was diluted with H₂O then extracted with EA. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 6%) to give benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(277.5 mg, 89% yield) as a solid. MS (ESI) m/z 723.4 [M+H]⁺.

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(277 mg, 0.383 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 30 min then concentrated to give benzyl(2-((4-aminobutyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(230 mg, 96% yield) as the TFA salt.

To a solution of benzyl(2-((4-aminobutyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(220 mg, 0.354 mmol, as TFA salt) in DMF (8 mL) at 0° C. was added K₂CO₃(146.4 mg, 1.06 mmol), followed by tert-butyl bromoacetate (68.9 mg,0.354 mmol). The mixture was stirred at RT for 4 h, then diluted withH₂O and extracted with DCM. The organic layer was concentrated to givethe crude product which was purified using silica gel eluting withMeOH/DCM (0% to 8%) to give tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(63 mg, 24% yield) as a solid. MS (ESI) m/z 737.3 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(63 mg, 0.086 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight then concentrated and dissolved in DMF (4 mL).3-(1-(Aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(35.7 mg, 0.128 mmol) and DIEA (33.0 mg, 0.256 mmol) were added. Thesolution was stirred for 5 min then HOBt (17.3 mg, 0.128 mmol) andEDCI.HCl (24.6 mg, 0.128 mmol) were added at the same time. The mixturewas stirred at RT overnight. The solvent was removed and the residue waspurified using prep-TLC eluting with DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(55 mg, 51% yield) as a solid. MS (ESI) m/z 943.2 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(55 mg, 0.058 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 30 min. The solvent was removedand the residue was dried to give the crude product which was dissolvedin DMF (2 mL) and adjusted to pH about 7 with TEA. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 38 (20.9 mg, 44% yield) as a solid.

Example 39 Compound 39:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (350 mg, 0.678 mmol) in DMF (4 mL) was added DIEA (262 mg, 2.03mmol), followed by tert-butyl (4-aminobutyl)carbamate (153 mg, 0.814mmol), HOBt (137 mg, 1.02 mmol) and EDCI.HCl (195 mg, 1.02 mmol) wasadded. The mixture was stirred at RT overnight, diluted with H₂O (10mL), and extracted with EA (15 mL×2). The combined organic layers werewashed with H₂O (10 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 71% yield) as a solid. MS (ESI) m/z 573.1 [M+H]⁺.

To a solution of tert-butyl(4-(2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)butyl)carbamate(240 mg, 0.42 mmol) in THF/H₂O (4 mL/1 mL) at 0° C. was added sodiumcarbonate (133 mg, 1.26 mmol), followed by benzyl chloroformate (108 mg,0.63 mmol) added. The mixture was stirred at RT for 2 h, diluted withH₂O (10 mL), and extracted with EA (15 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified using silica gel eluting with MeOH/DCM(0% to 6% to give benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 100% yield) as a solid. MS (ESI) m/z 707.1 [M+H]⁺.

To a solution of benzyl(2-((4-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoethyl)((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)carbamate(300 mg, 0.425 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (4 mL) and cooled to 0° C., then K₂CO₃ (196 mg,1.275 mmol) was added, followed by tert-butyl bromoacetate (83 mg, 0.425mmol). The mixture was stirred at RT for 16 h, diluted with H₂O andextracted with DCM. The organic layer was concentrated to give the crudeproduct which was purified using silica gel eluting with MeOH/DCM (0% to6% to give tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 44% yield) as solid. MS (ESI) m/z 721.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(135 mg, 0.188 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdried to give 4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (124.5 mg, crude) as the TFA salt. MS (ESI) m/z 665.4 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(70 mg, 0.185 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 2 h. The solvent was removed to give the amine TFAsalt which was dissolved in DMF (4 mL), then TEA (56 mg, 0.458 mmol) wasadded, followed by4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oicacid (123 mg, 0.185 mmol) and propanephosphonicacid anhydride (176 mg,0.554 mmol). The mixture was stirred at RT for 16 h. The solvent wasremoved and the residue was purified using prep-TLC (DCM/MeOH=10/1) togive benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(100 mg, 46% yield) as a solid. MS (ESI) m/z 926.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(50 mg, 0.054 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 1 h. The solvent was removed andthe residue was dried to give the crude product. It was dissolved in DMF(2 mL) and adjusted to pH about 7 with TEA. The solvent was removed andthe residue was purified using prep-HPLC as previously described toafford Compound 39 (31.4 mg, 64% yield) as a solid.

Example 40 Compound 40:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (300 mg, 0.56 mmol) in DCM (15 mL) at RT was added DIEA (216.7 mg,1.628 mmol), tert-butyl (2-aminoethyl)carbamate (99.2 mg, 0.62 mmol) andHATU (319.2 mg, 0.84 mmol). The mixture was stirred at RT for 3 h. Itwas concentrated and purified using silica gel eluting with MeOH/DCM (0to 7% to give tert-butyl(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)carbamate(324 mg, 100%) as an oil. MS (ESI) m/z 561.3 [M+H]⁺.

To a solution of tert-butyl(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)carbamate(324 mg, 0.578 mmol) in THF/H₂O (10 mL/3 mL) at RT was added sodiumcarbonate (184 mg, 1.734 mmol), followed by benzyl carbonochloridate(148 mg, 0.867 mmol) added. The mixture was stirred at RT for 0.5 h andthen the suspension was diluted with H₂O and extracted with EA. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with MeOH/DCM (0% to 5% to give benzyl(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(309 mg, 77% yield) as an oil. MS (ESI) m/z 695.3 [M+H]⁺.

To a solution of benzyl(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(309 mg, 0.445 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 0.5 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (12 mL) at RT, then K₂CO₃ (185 mg, 1.335 mmol) wasadded, followed by tert-butyl bromoacetate (87 mg, 0.445 mmol) added.The mixture was stirred at RT for 4 h. The mixture was diluted with H₂Oand extracted with DCM. The organic layer was concentrated to give thecrude product which was purified using prep-TLC eluting with DCM/MeOH(10:1) to give tert-butyl2-((2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)amino)acetate(103 mg, 33% yield). MS (ESI) m/z 575.3 [M+H]⁺.

To a solution of tert-butyl2-((2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)amino)acetate(103 mg, 0.145 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdried to give the intermediated product.3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(52 mg, 0.188 mmol) was dissolved in DMF (5 mL) and DIEA (56 mg, 0.435mmol) added. Then the intermediated product, HOBt (30 mg, 0.217 mmol)and EDCI.HCl (42 mg, 0.217 mmol) was added. The mixture was stirred atRT overnight. The solvent was removed and the residue was purified usingprep-TLC eluting with DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)amino)-2-oxoethyl)carbamate(110 mg, 83% yield) as a solid. MS (ESI) m/z 914.3 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)amino)-2-oxoethyl)carbamate(110 mg, 0.120 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 0.5 h. The solvent was removedand the residue was dried to give the crude product which was dissolvedin DMF (2 mL) and adjusted to a pH of about 7 with TEA. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 40 (28.5 mg, 31% yield) as a solid.

Example 41 Compound 41:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3,18-dioxo-8,11,14-trioxa-2,5,17-triazanonadecan-19-yl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (400 mg, 0.91 mmol) in DMF (10 mL)at RT was added DIEA (352 mg, 2.73 mmol), followed by tert-butyl(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl) carbamate (320 mg, 1.09mmol), HOBt (185 mg, 1.37 mmol) and EDCI.HCl (263 mg, 1.37 mmol) wereadded. The mixture was stirred at RT overnight, diluted with H₂O andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 10%) togive tert-butyl(1-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(538 mg, 83% yield) as an oil. MS (ESI) m/z 713.3 [M+H]⁺.

To a solution of tert-butyl(1-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(538 mg, 0.76 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (7 mL) and cooled to 0° C., then K₂CO₃ (210 mg,1.52 mmol) was added, followed by tert-butyl bromoacetate (132 mg, 0.68mmol) added. The mixture was stirred at RT for 6 h. The mixture wasdiluted with H₂O and extracted with DCM. The organic layer wasconcentrated to give the crude product which was purified using prep-TLCeluting with DCM/MeOH (10:1) to give tert-butyl17-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-16-oxo-6,9,12-trioxa-3,15-diazaheptadecan-1-oate(137 mg, 25% yield) as a solid. MS (ESI) m/z 727.3 [M+H]⁺.

To a solution of tert-butyl 17-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-16-oxo-6,9,12-trioxa-3,15-diazaheptadecan-1-oate(65 mg, 0.09 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h. The solvent was removed and the residue was driedto give acid as an oil which was dissolved in DMF (4 mL) and then addedDIEA (35 mg, 0.27 mmol), followed by3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(31 mg, 0.11 mmol), HOBt (18 mg, 0.135 mmol) and EDCI.HCl (26 mg, 0.135mmol). The mixture was stirred at RT overnight, diluted with H₂O andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using prep-HPLC as previously described to affordCompound 41 (2.0 mg, 2% yield) as a solid.

Example 42 Compound 42:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,18-dioxo-8,11,14-trioxa-2,5,17-triazanonadecan-19-yl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetic acid (400 mg, 0.91 mmol) in DMF (10 mL)at RT was added DIEA (352 mg, 2.73 mmol), followed by tert-butyl(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl) carbamate (320 mg, 1.09mmol), HOBt (185 mg, 1.37 mmol) and EDCI.HCl (263 mg, 1.37 mmol) wereadded. The mixture was stirred at RT overnight, diluted with H₂O andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 10%) togive tert-butyl(1-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(538 mg, 83% yield) as an oil. MS (ESI) m/z 713.3 [M+H]⁺.

To a solution of tert-butyl(1-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(538 mg, 0.76 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (7 mL) and cooled to 0° C., then K₂CO₃ (210 mg,1.52 mmol) was added, followed by tert-butyl bromoacetate (132 mg, 0.68mmol) added. The mixture was stirred at RT for 6 h. The mixture wasdiluted with H₂O and extracted with DCM. The organic layer wasconcentrated to give the crude product which was purified using prep-TLCeluting with DCM/MeOH (10:1) to give tert-butyl17-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-16-oxo-6,9,12-trioxa-3,15-diazaheptadecan-1-oate(137 mg, 25% yield) as a solid. MS (ESI) m/z 727.3 [M+H]⁺.

To a solution of tert-butyl17-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)-16-oxo-6,9,12-trioxa-3,15-diazaheptadecan-1-oate(72 mg, 0.10 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h. The solvent was removed and the residue was driedto give acid as an oil. It was dissolved in DMF (4 mL) and DIEA (38.7mg, 0.30 mmol) was added. Then3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(31 mg, 0.11 mmol), HOBt (18 mg, 0.135 mmol) and EDCI.HCl (26 mg, 0.135mmol) were added. The mixture was stirred at RT overnight, diluted withH₂O and extracted with EA. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified using prep-HPLC as previously described toafford Compound 42 (25.1 mg, 27% yield) as a solid.

Example 43 Compound 43:14-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-6,9,12-trioxa-3-azatetradecanamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (400 mg, 0.752 mmol) in N, N-dimethylformamide (12 mL) was added N,N-diisopropylethylamine (291 mg, 2.253 mmol), followed by tert-butyl(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)carbamate (264 mg, 0.901mmol), HOBt (152 mg, 1.126 mmol) and EDCI.HCl (216 mg, 1.126 mmol). Themixture was stirred at RT overnight, diluted with H₂O and extracted withEA. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to givetert-butyl(1-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(452 mg, 87% yield) as an oil. MS (ESI) m/z 693.2 [M+H]⁺.

To a solution of tert-butyl(1-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamate(452 mg, 0.653 mmol) in THF/H₂O (10 mL/3 mL) at RT was added sodiumcarbonate (207 mg, 1.959 mmol), followed by benzyl chloroformate (167mg, 0.980 mmol) added. The mixture was stirred at RT for 30 min, dilutedwith H₂O and extracted with EA. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified using silica gel eluting with MeOH/DCM (0% to 6% to givebenzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazanonadecan-19-yl)carbamate(487 mg, 90% yield) as an oil. MS (ESI) m/z 827.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazanonadecan-19-yl)carbamate(487 mg, 0.589 mmol) in DCM (12 mL) was added TFA (3 mL). The mixturewas stirred at RT for 0.5 h then concentrated. The resulting amine TFAsalt was dissolved in DMF (10 mL) and at RT was added K₂CO₃ (249 mg,1.80 mmol), followed by tert-butyl bromoacetate (106 mg, 0.54 mmol)added. The mixture was stirred at RT for 3 h. The mixture was dilutedwith H₂O and extracted with DCM. The organic layer was concentrated togive the crude product which was purified using prep-TLC eluting withDCM/MeOH (10:1) to give tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2,10,13,16-tetraoxa-4,7,19-triazahenicosan-2i-oate(169 mg, 39% yield) as an oil. MS (ESI) m/z 841.4 [M+H]⁺.

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2,10,13,16-tetraoxa-4,7,19-triazahenicosan-2i-oate(169 mg, 0.201 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdried to give the intermediated acid as an oil, which was dissolved inDMF (6 mL) and DIEA (77.4 mg, 0.600 mmol) was added. Then HOBt (40.5 mg,0.300 mmol), EDCI.HCl (57.6 mg, 0.300 mmol) and3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(72.5 mg, 0.260 mmol) were added. The mixture was stirred at RTovernight. The solvent was removed and the residue was purified usingprep-TLC eluting with DCM/MeOH (10:1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,18-dioxo-8,11,14-trioxa-2,5,17-triazanonadecan-19-yl)carbamate(109 mg, 52% yield) as an oil. MS (ESI) m/z 1046.6 [M+H]⁺.

To a solution of compound benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,18-dioxo-8,11,14-trioxa-2,5,17-triazanonadecan-19-yl)carbamate(109 mg, 0.104 mmol) in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5mL). The mixture was stirred at RT for 0.5 h. The solvent was removedand the residue was dried to give the crude product which was dissolvedin DMF (2 mL) and adjusted to a pH of about 7 with TEA. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 43 (28 mg, 30% yield) as a solid.

Example 44 Compound 44:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-8-methyl-3,12-dioxo-2,5,8,11-tetraazatridecan-13-yl)piperidine-4-carboxamide

To a solution of tert-butyl(2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)carbamate(Synthetic procedure see Example 15) (400 mg, 0.628 mmol) in DCM (4 mL)was added TFA (1 mL). The mixture was stirred at RT for 0.5 h. Thesolvent was removed and the residue was dried to give1-(2-((2-((2-aminoethyl)(methyl)amino)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideas the TFA salt. MS (ESI) m/z 538.2 [M+H]⁺.

To a solution of1-(2-((2-((2-aminoethyl)(methyl)amino)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(480 mg, as the TFA salt) in DMF (10 mL) at RT was added tert-butyl2-bromoacetate (144 mg, 0.74 mmol) and K₂CO₃ (153 mg, 1.11 mmol), thenthe mixture was stirred at RT for 5 h. The mixture was then diluted withH₂O and extracted with EA. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with DCM/MeOH (0% to 10%) to givetert-butyl2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)acetate(110 mg, 22% yield) as a solid. MS (ESI) m/z 651.2 [M+H]⁺.

To a solution of tert-butyl2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)acetate(60 mg, 0.093 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixturewas stirred at RT for 3 h. The solvent was removed and the residue wasdried to give2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)aceticacid (80 mg, crude) as an oil. MS (ESI) m/z 509.2 [M+H]⁺.

To a solution of2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)aceticacid (75 mg, 0.126 mmol) in DMF (4 mL) was added TEA (38 mg, 0.378mmol), then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(75 mg, 0.126 mmol) and propanephosphonic acid anhydride (120 mg, 0.378mmol) were added. The mixture was stirred at RT for 2 h. The solvent wasremoved and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to afford Compound 44 (35 mg, 32% yield) as a solid.

Example 45 Compound 45:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)ethyl)acetamide

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (250 mg, 0.469 mmol) in DMF (6 mL) was added DIEA (181.5 mg, 1.407mmol), followed by tert-butyl (2-aminoethyl)carbamate (90.2 mg, 0.563mmol), HOBt (95 mg, 0.703 mmol) and EDCI.HCl (135 mg, 0.703 mmol) wereadded. The mixture was stirred at RT overnight, diluted with H₂O andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 10%) togive tert-butyl(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)carbamate(174 mg, 66% yield) as an oil. MS (ESI) m/z 561.1 [M+H]⁺.

To a solution of tert-butyl(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetamido)ethyl)carbamate(174 mg, 0.310 mmol) in THF/H₂O (8 mL/2.4 mL) at RT was added sodiumcarbonate (98.5 mg, 0.930 mmol), followed by benzyl chloroformate (79.5mg, 0.466 mmol) added. The mixture was stirred at RT for 1 h, dilutedwith H₂O (10 mL), and extracted with EA (15 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified using silica gel eluting with MeOH/DCM(0% to 6% to give benzyl(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(189 mg, 88% yield) as an oil. MS (ESI) m/z 695.2 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(103 mg, 0.272 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). Themixture was stirred at RT for 1 h and concentrated to give the amine TFAsalt which was dissolved in THF (4 mL) and TEA (60.3 mg, 0.597 mmol) wasadded. Then 4-nitrobenzyl chloroformate (60.2 mg, 0.299 mmol) was added.The mixture was stirred at RT for 30 min. The solvent was removed togive the crude 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(120 mg, crude). MS (ESI) m/z 445.4 [M+H]⁺.

To a solution of benzyl(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(189 mg, 0.272 mmol) in DCM (8 mL) at RT was added TFA (2 mL). Themixture was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt which was dissolved in THF(5 mL) and TEA (82.4 mg, 0.816 mmol) was added. The mixture was stirredat RT for 5 min. Then the suspension of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(120 mg, crude) in THF (1 mL) was added and the mixture was stirred atRT for 12 h. The mixture was then diluted with H₂O and extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with EA in PE from 10% to 50% to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)ethyl)amino)-2-oxoethyl)carbamate(159 mg, 66% yield) as an oil. MS (ESI) m/z 900.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)ethyl)amino)-2-oxoethyl)carbamate(159 mg, 0.176 mmol) in AcOH (2 mL) at RT was added HBr (33% in AcOH, 2mL). The mixture was stirred at RT for 30 min. The solvent was removedand the residue was dried to give the crude product which was dissolvedin DMF (2 mL) and adjusted to a pH of about 7 with TEA. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 45 (33.6 mg, 25% yield) as a solid.

Example 46 Compound 46:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3-oxo-7,10,13-trioxa-2,4-diazapentadecan-15-yl)acetamide

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(100 mg, 0.263 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). Themixture was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the amine TFA salt, which was dissolved in THF(5 mL) and TEA (58 mg, 0.578 mmol) was added. Then 4-nitrobenzylchloroformate (58 mg, 0.289 mmol) was added. The mixture was stirred atRT for 0.5 h. The solvent was removed to give the crude 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(116 mg, crude). MS (ESI) m/z 445.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazanonadecan-19-yl)carbamate(synthetic procedure see Example 43) (269 mg, 0.325 mmol) in DCM (12 mL)at RT was added TFA (3 mL). The mixture was stirred at RT for 1 h thenconcentrated. The resulting amine TFA salt was dissolved in THF (4 mL)and TEA (48.4 mg, 0.479 mmol) was added. The mixture was stirred at RTfor 5 min. Then the suspension of 4-nitrophenyl((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate(61 mg) in THF (1 mL) was added and the mixture was stirred at RT for 12h. The mixture was then diluted with H₂O and extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel eluting with EA in PE from 10% to 50% to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,17-dioxo-7,10,13-trioxa-2,4,16-triazaoctadecan-18-yl)carbamate(112 mg, 79% yield) as an oil. MS (ESI) m/z 1032.6 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-3,17-dioxo-7,10,13-trioxa-2,4,16-triazaoctadecan-18-yl)carbamate(112 mg, 0.108 mmol) in AcOH (2 mL) at RT was added HBr (33% in AcOH, 2mL). The mixture was stirred at RT for 30 min. The solvent was removedand the residue was dried to give the crude product, which was dissolvedin DMF (2 mL) and adjusted to a pH of about 7 with TEA. The solvent wasremoved and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 46 (34.9 mg, 36% yield) as a solid.

Example 47 Compound 47:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-8-methyl-3,12-dioxo-2,5,8,11-tetraazatridecan-13-yl)piperidine-4-carboxamide

To a solution of tert-butyl(2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)carbamate(synthetic procedure see Example 15) (400 mg, 0.628 mmol) in DCM (4 mL)was added TFA (1 mL). The mixture was stirred at RT for 0.5 h. Thesolvent was removed and the residue was dried to give1-(2-((2-((2-aminoethyl)(methyl)amino)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamideas the TFA salt. MS (ESI) m/z 538.2 [M+H]⁺.

To a solution of1-(2-((2-((2-aminoethyl)(methyl)amino)ethyl)amino)-2-oxoethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide(480 mg, as the TFA salt) in DMF (10 mL) at RT was added tert-butyl2-bromoacetate (144 mg, 0.74 mmol) and K₂CO₃ (153 mg, 1.11 mmol), thenthe mixture was stirred at RT for 5 h. The mixture was then diluted withH₂O and extracted with EA. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified using silica gel eluting with DCM/MeOH (0% to 10%) to givetert-butyl2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)acetate(110 mg, 22% yield) as a solid. MS (ESI) m/z 651.2 [M+H]⁺.

To a solution of tert-butyl2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)acetate(60 mg, 0.093 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixturewas stirred at RT for 3 h. The solvent was removed and the residue wasdried to give2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)aceticacid (80 mg, crude) as an oil. MS (ESI) m/z 509.2 [M+H]⁺.

To a solution of2-((2-((2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)ethyl)(methyl)amino)ethyl)amino)aceticacid (120 mg, 0.202 mmol) in DMF (5 mL) was added TEA (51 mg, 0.505mmol) then3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(80 mg, 0.242 mmol) and propanephosphonicacid anhydride (160 mg, 0.505mmol) were added. The mixture was stirred at RT for 2 h. The solvent wasremoved and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to afford Compound 47 (14.6 mg, 8% yield) as a solid.

Example 48 Compound 48:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of tert-butyl4-((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(synthetic procedure see Example 36) (166 mg, 0.23 mmol) in DCM (4 mL)was added TFA (1 mL). The mixture was stirred at RT for 1 h thenconcentrated. The resulting amine TFA salt was dissolved in DMF (5 mL)and DIEA (89 mg, 0.69 mmol) added. Then1-(aminomethyl)-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(84 mg, 0.23 mmol), HOBt (39 mg, 0.29 mmol) and EDCI.HCl (56 mg, 0.29mmol) were added. The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to give benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(110 mg, 51% yield) as a solid. MS (ESI) m/z 940.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(110 mg, 0.117 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h. The solvent was removed and theresidue was dried to give the crude product, which was dissolved in DMF(2 mL) and adjusted to a pH of about 7 with TEA. The solvent was removedand the residue was purified using prep-HPLC as previously described toafford Compound 48 (36.8 mg, 39% yield) as a solid.

Example 49 Compound 49:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide

To a solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(200 mg, 0.56 mmol) in N, N-dimethylformamide (8 mL) at RT was addedpotassium carbonate (155 mg, 1.12 mmol) and tert-butyl 2-bromoacetate(129 mg, 0.67 mmol) added. After 7 h, the mixture was diluted with H₂Oand extracted with EA. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified using silica gel eluting with MeOH/DCM (0%to 10%) to give tert-butyl2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetate(196 mg, 74% yield) as an oil. MS (ESI) m/z 475.3 [M+H]⁺.

To a solution of tert-butyl2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)acetate(85 mg, 0.18 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdissolved in tert-butyl methyl ether (5 mL). After 30 min, thesuspension was filtered and the filter cake was dried in vacuum to give2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (75 mg, crude) as trifluoroacetate salt. MS (ESI) m/z 419.2 [M+H]⁺.

To a solution of2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (75 mg, 0.18 mmol) in N, N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (46 mg, 0.36 mmol),4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(82 mg, 0.18 mmol), HOBt (36 mg, 0.27 mmol) and EDCI.HCl (52 mg, 0.27mmol). The mixture was stirred at RT overnight. The solvent was removedand the residue was purified using prep-HPLC as previously described toafford Compound 49 (24.3 mg, 16% yield) as a solid.

Example 50 Compound 50:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamido

To a solution of(1r,4r)-N¹-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine(200 mg, 0.58 mmol) in N, N-dimethylformamide (8 mL) at RT was addedpotassium carbonate (160 mg, 1.16 mmol) and tert-butyl 2-bromoacetate(134 mg, 0.69 mmol). After 7 h, the mixture was diluted with H₂O andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 10%) togive tert-butyl2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetate(188 mg, 71% yield) as an oil. MS (ESI) m/z 459.3 [M+H]⁺.

To a solution of tert-butyl2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)acetate(124 mg, 0.27 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at RT overnight. The solvent was removed and the residue wasdissolved in tert-butyl methyl ether (5 mL). After 30 min, thesuspension was filtered and the filter cake was dried in vacuum to give2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (108 mg, crude) as trifluoroacetate salt. MS (ESI) m/z 403.2[M+H]⁺.

To a solution of2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)aceticacid (108 mg, 0.27 mmol) in N, N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (69 mg, 0.54 mmol),4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(122 mg, 0.27 mmol), HOBt (55 mg, 0.41 mmol) and EDCI.HCl (78 mg, 0.41mmol). The mixture was stirred at RT overnight. The solvent was removedand the residue was purified using prep-HPLC as previously described toafford Compound 50 (39.9 mg, 18% yield) as a solid.

Example 51 Compound 51:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of tert-butyl4-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-3,6-dioxo-1-phenyl-2-oxa-4,7,12-triazatetradecan-14-oate(see experimental for Compound 36) (214 mg, 0.29 mmol) in DCM (4 mL) wasadded TFA (1 mL). The mixture was stirred at RT for 1 h thenconcentrated. The resulting amine TFA salt was dissolved in DMF (5 mL)and DIEA (93 mg, 0.722 mmol) added. Then1-(aminomethyl)-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(162 mg, 0.55 mmol), HOBt (50 mg, 0.36 mmol) and EDCI.HCl (70 mg, 0.36mmol) were added. The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using prep-TLC eluting withDCM/MeOH (10:1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(185 mg, 67% yield) as a solid. MS (ESI) m/z 956.4 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-((4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)amino)-2-oxoethyl)carbamate(185 mg, 0.19 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h then concentrated, dissolved inDMF (2 mL), and adjusted to a pH of about 7 with TEA. The mixture wasconcentrated and the residue was purified using prep-HPLC as previouslydescribed to afford Compound 51 (25.4 mg, 16% yield) as a solid.

Example 52 Compound 52:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((3-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)propyl)amino)-2-oxoethyl)piperidine-4-carboxamide

To a solution of2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)aceticacid (250 mg, 0.452 mmol) in DMF (5 mL) was added DIEA (174.9 mg, 1.356mmol), followed by tert-butyl (3-aminopropyl)carbamate (117.9 mg, 0.678mmol) and HATU (343.5 mg, 0.904 mmol). The mixture was stirred at RT for2 h, diluted with H₂O and extracted with EA. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive the crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give tert-butyl(3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)carbamate(234 mg, 87% yield) as a solid. MS (ESI) m/z 595.7 [M+H]⁺.

To a solution of tert-butyl(3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)carbamate(234 mg, 0.393 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in DMF (5 mL) at RT, then K₂CO₃ (162 mg, 1.179 mmol) wasadded, followed by tert-butyl bromoacetate (76 mg, 0.393 mmol). Themixture was stirred at RT overnight, diluted with H₂O and extracted withDCM. The organic layer was concentrated to give the crude product whichwas purified using silica gel eluting with MeOH/DCM (0% to 10%) to givetert-butyl2-((3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)amino)acetate(70 mg, 29% yield) as an oil. MS (ESI) m/z 609.8 [M+H]⁺.

To a solution of tert-butyl2-((3-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)acetamido)propyl)amino)acetate(70 mg, 0.114 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT overnight then concentrated, and the residue was dissolvedin DMF (2 mL). DIEA (44.1 mg, 0.342 mmol) was added followed by3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(36 mg, 0.114 mmol) and HATU (86.6 mg, 0.228 mmol). The mixture wasstirred at RT for 2 h. The solvent was removed and the residue waspurified using prep-HPLC as previously described to afford Compound 52(16 mg, 17% yield) as a solid.

Example 53 Compound 53:2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide

To a solution of compound 7-((tert-butoxycarbonyl)amino)heptanoic acid(1.0 g, 4.08 mmol) in DCM (20 mL) at RT was added EDAC.HCl (1.17 g, 6.12mmol) and TEA (824 mg, 8.16 mmol) followed by N,O-dimethylhydroxylamine(437 mg, 4.48 mmol) and N,N-dimethylpyridin-4-amine (52 mg, 0.408 mmol).The mixture was stirred at RT overnight then diluted with water andextracted with DCM. The organic layers were dried over Na₂SO₄, filtered,and concentrated. The residue was purified using silica gel eluting withMeOH/DCM (0% to 8%) to give tert-butyl(7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate (1.071 g, 91% yield) asan oil. MS (ESI) m/z 289.2 [M+H]⁺.

Tert-butyl (7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate (1.07 g, 3.72mmol) was dissolved in THF (20 mL) and cooled to −70° C., then lithiumaluminium hydride (5.6 mL, 1 M in THF) was added slowly. After addition,the solution was warmed to 0° C. and stirred at this temperature for 30min then was quenched with saturated ammonium chloride and extractedwith EA. The organic layers were dried over Na₂SO₄, filtered andconcentrated to give tert-butyl (7-oxoheptyl)carbamate (839 mg crude).MS (ESI) m/z 252.2 [M+Na]⁺.

To a stirred solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(450 mg, 1.25 mmol) and tert-butyl (7-oxoheptyl)carbamate (290 mg, 1.25mmol) in MeOH (20 mL) was added AcOH (4 drops) followed by sodiumcyanoborohydride (315 mg, 5 mmol). The mixture was stirred at RT for 4 hthen concentrated and the residue was purified using prep-TLC elutingwith DCM/MeOH (10:1) to give tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)carbamate(440 mg, 61% yield) as a solid. MS (ESI) m/z=574.4 [M+H]⁺.

To a stirred solution of tert-butyl(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)carbamate(440 mg, 0.77 mmol) in THF (7 mL) and water (0.4 mL) was added sodiumcarbonate (244 mg, 2.3 mmol) and benzyl chloroformate (200 mg, 1.17mmol). The mixture was stirred at RT for 2 h then water was added andthe mixture was extracted with EA. The organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to give benzyl(7-((tert-butoxycarbonyl)amino)heptyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(590 mg crude) as an oil. MS (ESI) m/z=708.4 [M+H]⁺.

To a stirred solution of benzyl(7-((tert-butoxycarbonyl)amino)heptyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(0.83 mmol) in DCM (8 mL) was added TFA (4 mL). The mixture was stirredat RT for 2 h then concentrated, dissolved in DMF (2 mL), and adjustedto a pH of about 7 with aqueous K₂CO₃. The mixture was concentrated andthe residue was purified using prep-TLC eluting with DCM/MeOH (10:1) togive benzyl(7-aminoheptyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(210 mg) as a solid. MS (ESI) m/z=608.4 [M+H]⁺.

To a stirred solution of benzyl(7-aminoheptyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(210 mg, 0.34 mmol) in DMF (4 mL) was added K₂CO₃ (71 mg, 0.51 mmol) andtert-butyl 2-bromoacetate (67 mg, 0.34 mmol). The mixture was stirred atRT for 2 h then water was added and the mixture was extracted with EA.The organic layers were washed with brine, dried over Na₂SO₄, evaporatedand purified using prep-TLC (EA) to give tert-butyl2-((7-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)acetate(80 mg, 32% yield) as an oil. MS (ESI) m/z=722.4 [M+H]⁺.

To a stirred solution of tert-butyl2-((7-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)acetate(80 mg, 0.11 mmol) in DCM (6 mL) was added TFA (1.5 mL). The mixture wasstirred at RT overnight then concentrated to give crude2-((7-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)aceticacid. MS (ESI) m/z=666.4 [M+H]⁺.

To a stirred solution of2-((7-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)aceticacid (0.11 mmol, crude) and3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dionehydrochloride (42 mg, 0.13 mmol) in DMF (5 mL) was added DIEA (43 mg,0.33 mmol), HOBt (23 mg, 0.17 mmol) and EDCI.HCl (33 mg, 0.17 mmol). Themixture was stirred at RT overnight then water was added and the mixtureand extracted with EA. The combined organic layers were washed withbrine, dried over Na₂SO₄, evaporated and purified using prep-TLC elutingwith DCM/MeOH (10/1) to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)heptyl)carbamate(40 mg, 39% yield) as a solid. MS (ESI) m/z=464.3 [M/2+H]⁺.

To a stirred solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)heptyl)carbamate(40 mg, 0.043 mmol) in AcOH (1 mL) was added HBr in AcOH (1 mL). Themixture was stirred at RT for 30 min then concentrated. The residue wasdissolved in DMF, adjusted to a pH of about 7 with TEA, then evaporatedand purified using prep-HPLC as previously described to afford Compound53 (9.3 mg, 27% yield) as a solid.

Example 54 Compound 54:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(2-((4-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)butyl)amino)-2-oxoethyl)piperidine-4-carboxamide

Compound 54 was prepared following similar procedure described inExamples 1 and 67.

Example 55 Compound 55:2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide

Compound 55 was prepared following similar procedure described inExample 49.

Example 56 Compound 56:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide

Compound 56 was prepared following similar procedure described inExample 50.

Example 57 Compound 57:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(7-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)heptyl)piperidine-4-carboxamide

Compound 57 was prepared following similar procedure described inExamples 20 and 33.

Example 58 Compound 58:N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3-oxo-8,11,14,17-tetraoxa-2,5-diazanonadecan-19-yl)piperidine-4-carboxamide

Compound 58 was prepared following similar procedure described inExamples 31 and 34.

Example 59 Compound 59:1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

Compound 59 was prepared following similar procedure described inExample 23.

Example 60 Compound 60:2-((5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)amino)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide

Compound 60 was prepared following similar procedure described inExamples 53.

Example 61 Compound 61:1-(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)-3-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)urea

To a solution of tert-butyl(8-(methoxy(methyl)amino)-8-oxooctyl)carbamate (700 mg, 2.317 mmol) inTHF (10 mL) at −78° C. was added LiAlH₄ (3.4 mL, 1 M in THF) dropwiseover 10 min, the mixture was stirred at 0° C. for 30 min. The mixturewas then quenched with saturated aqueous NH₄Cl (5 mL) slowly. Themixture was extracted with EA and the combined organic phase was washedwith H₂O, dried over Na₂SO₄, filtered and concentrated to givetert-butyl (8-oxooctyl)carbamate (583 mg, crude).

To a solution of(1r,4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(300 mg, 0.833 mmol) in MeOH/HOAc (10 mL:1 mL) at RT was addedtert-butyl (8-oxooctyl)carbamate (404 mg, 1.666 mmol), followed byNaBH₃CN (210 mg, 3.332 mmol). The suspension was stirred at RTovernight. The solvent was removed and the residue was purified usingsilica gel eluting with MeOH/DCM (0% to 4%) to give tert-butyl(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(331 mg, 68% yield) as an oil. MS (ESI) m/z 588.2 [M+H]⁺.

To a solution of tert-butyl(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)octyl)carbamate(331 mg, 0.563 mmol) in THF/H₂O (5 mL:1.5 mL) at RT was added sodiumcarbonate (180 mg, 1.689 mmol), followed by benzyl carbonochloridate(288 mg, 1.689 mmol). The mixture was stirred at RT for 1 h then thesuspension was diluted with H₂O and extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to givethe crude product, which was purified using silica gel eluting withMeOH/DCM (0% to 5%) to give benzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(327 mg, 81% yield) as an oil. MS (ESI) m/z 722.4 [M+H]⁺.

To a solution of benzyl(8-((tert-butoxycarbonyl)amino)octyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(327 mg, 0.453 mmol) in DCM (12 mL) at RT was added TFA (3 mL). Themixture was stirred at RT for 2 h then concentrated to give crude benzyl(8-aminooctyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamateas the TFA salt. MS (ESI) m/z 622.3 [M+H]⁺.

3-(7-(aminomethyl)-2-methyl-4-oxothieno[3,4-d]pyrimidin-3(4H)-yl)piperidine-2,6-dione(103 mg, 0.246 mmol) was dissolved in THF (2 mL) and TEA (49 mg, 0.295mmol) was added. Then 4-nitrobenzyl chloroformate (59 mg, 0.295 mmol)was added. The mixture was stirred at RT for 0.5 h then concentrated togive crude 4-nitrophenyl((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)carbamate(115 mg, crude). MS (ESI) m/z 471.4 [M+H]⁺.

Benzyl(8-aminooctyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(120 mg, 0.164 mmol) was dissolved in THF (2 mL) and TEA (83 mg, 0.820mmol) was added. The mixture was stirred at RT for 5 min. Then thesuspension of 4-nitrophenyl((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)carbamate(115 mg, crude) in THF (1 mL) was added and the mixture was stirred at25° C. for 3 h. The mixture was diluted with H₂O and extracted with DCM.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified using silicagel to give benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(3-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)ureido)octyl)carbamate(100 mg) as an oil. MS (ESI) m/z 954.5 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(8-(3-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)ureido)octyl)carbamate(100 mg, 0.104 mmol) in AcOH (1.5 mL) at RT was added HBr (33% in AcOH,1.5 mL). The mixture was stirred at RT for 30 min then concentrated,dissolved in DMF (2 mL), and adjusted to a pH of about 7 with TEA. Themixture was concentrated and the residue was purified using prep-HPLC aspreviously described to afford Compound 61 (17.8 mg, 21% yield) as asolid.

Example 62 Compound 62:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-N-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-5,8,11-trioxa-2-azatridecan-13-yl)acetamide

Compound 62 was prepared following similar procedure described inExamples 21 and 43.

Example 63 Compound 63:2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2-yl)amino)cyclohexyl)amino)-N-(2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)acetamide

Compound 63 was prepared following similar procedure described inExample 36.

Example 64 Compound 64:4-((14-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 64 was prepared following similar procedure described inExamples 10 and 22.

Example 65 Compound 65:1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,5-triazin-2-yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

Compound 65 was prepared following similar procedure described inExample 22.

Example 66 Compound 66:3-(2-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione

Compound 66 was prepared following similar procedure described inExamples 53.

Example 67 Compound 67:(S)-3-(1-((4-(((2-(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

To a solution of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oicacid (1.5 g, 5.7 mmol) in DCM (25 mL) at RT was added EDCI.HCl (1.64 g,8.56 mmol) and TEA (1.15 g, 11.4 mmol). Then N,O-dimethylhydroxylamine(611 mg, 6.27 mmol) and N,N-dimethylpyridin-4-amine (69 mg, 0.57 mmol)were added and the mixture was stirred at RT overnight. The mixture wasdiluted with H₂O and extracted with DCM. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified using silica gel eluting with MeOH/DCM (0%to 5%) to give tert-butyl(3-methyl-4-oxo-2,6,9-trioxa-3-azaundecan-11-yl)carbamate (1.42 g, 82%yield) as an oil. MS (ESI) m/z 307.2 [M+H]⁺, 207.2 [M-Boc]⁺.

To a solution of tert-butyl(3-methyl-4-oxo-2,6,9-trioxa-3-azaundecan-11-yl)carbamate (500 mg, 1.64mmol) in THF (15 mL) at −78° C. was added LiAlH₄ (3.28 mL, 1 M in THF)dropwise over 10 min. The mixture was stirred at 0° C. for 30 min thenquenched with saturated NH₄Cl (5 mL) aqueous slowly. The mixture wasextracted with EA and washed with brine. The organic layer was driedover Na₂SO₄, filtered and concentrated to give tert-butyl(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (320 mg, crude).

To a solution of(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(300 mg, 0.693 mmol, HCl salt) in MeOH (10 mL) at RT was added DIEA (89mg, 0.693 mmol). The solution was stirred at RT for 10 min. Thentert-butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (205 mg, 0.831mmol) and NaBH₃CN (174 mg, 2.772 mmol) were added, followed by AcOH (2drops). The suspension was stirred at RT overnight. The solvent wasremoved and the residue was purified using silica gel eluting withMeOH/DCM (0% to 8%) to give tert-butyl(2-(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)ethoxy)ethyl)carbamate(206 mg, 50% yield) as an oil. MS (ESI) m/z 592.3 [M+H]⁺.

To a solution of tert-butyl(2-(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)ethoxy)ethyl)carbamate(100 mg, 0.169 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture wasstirred at RT for 1 h then concentrated. The resulting amine TFA saltwas dissolved in MeOH/DCM (1 mL:4 mL) and cooled to 0° C., then DIEA (89mg, 0.693 mmol) was added and the mixture was stirred for 5 min. Then(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzaldehyde(65 mg, 0.169 mmol) and NaBH₃CN (43 mg, 0.676 mmol) were added, followedby AcOH (2 drops). The mixture was stirred at RT overnight. The solventwas removed and the residue was purified using silica gel eluting withMeOH/DCM (0% to 10%) to give the crude product (80 mg). It was furtherpurified using prep-HPLC as previously described to afford Compound 67(29.2 mg, 24% yield) as a solid.

Example 68 Compound 68:(S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

Compound 68 was prepared following similar procedure described inExample 67.

Example 69 Compound 69:(S)-3-(1-((4-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

Compound 68 was prepared following similar procedure described inExample 67.

Example 70 Compound 70:3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(4-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg,0.882 mmol) in DMF (18 ml) at RT was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(742 mg, 2.401 mmol) and K₂CO₃ (365.3 mg, 2.647 mmol). The suspensionwas bubbled with N₂. Then Pd(dppf)Cl₂ (322.8 mg, 0.441 mmol) was addedand the mixture was stirred at 100° C. for 16 h. The mixture wasfiltered and concentrated to afford a residue, which was purified usingsilica gel eluting with EA/PE (0% to 60%) to give tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(192 mg, 49% yield) as a solid. MS (ESI) m/z 388.1 [M-55]⁺.

To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(192 mg, 0.433 mmol) in DCM/MeOH (1 m1:6 mL) at RT was added Pd/C (200mg). The mixture was degassed and refilled with H₂ then stirred at RTfor 18 h. The mixture was filtered and the filtrate was concentrated togive crude tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidine-1-carboxylate(181 mg, 94% yield). MS (ESI) m/z 390.1 [M-55]⁺.

To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidine-1-carboxylate(181 mg, 0.407 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at RT for 1 h then concentrated to give crude3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dioneas a TFA salt. MS (ESI) m/z 346.1 [M+H]⁺.

To a solution of(1r,4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(400 mg, 0.924 mmol) in DMF (20 mL) at RT was added K₂CO₃ (382.4 mg,2.771 mmol) and 7-bromo-N-methoxy-N-methylheptanamide (232 mg, 0.924mmol). The mixture was stirred at 75° C. overnight. The mixture wasdiluted with H₂O and extracted with DCM. The combined organic phase wasdried over Na₂SO₄, filtered, evaporated to afford a residue which waspurified using silica gel eluting with MeOH/DCM (0% to 10%) to give7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-methoxy-N-methylheptanamide(173 mg, 35% yield) as an oil. MS (ESI) m/z 532.3 [M+H]⁺.

To a solution of7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-N-methoxy-N-methylheptanamide(173 mg, 0.326 mmol) in THF/H₂O (8 mL:2 mL) at RT was added sodiumcarbonate (103.6 mg, 0.977 mmol), followed by benzyl chloroformate (66.7mg, 0.391 mmol). The mixture was stirred at RT for 1 h. The mixture wasdiluted with H₂O and extracted with EA. The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified using silica gel eluting with MeOH/DCM (0% to 4%) togive benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate(192 mg, 89% yield) as an oil. MS (ESI) m/z 666.3 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate(96 mg,0.1443 mmol) in THF (5 mL) at −78° C. was added LiAlH₄ (0.22 mL,1M in THF) dropwise under N₂. After addition, the mixture was stirred at−78° C. for 30 min. The mixture was quenched with sat. NH₄Cl (5 mL) andextracted with EA. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give crude benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-oxoheptyl)carbamate.MS (ESI) m/z 607.3 [M+H]⁺.

To a solution of3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(60.6 mg, 0.132 mmol) in DCM/MeOH (8 mL:2 mL) at RT was added DIEA (17.0mg, 0.132 mmol). After 3 min, benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-oxoheptyl)carbamate(80 mg. 0.132 mmol), NaBH₃CN (33.3 mg, 0.528 mmol) and AcOH (2 drops)were added. The mixture was stirred at RT for 5 h then concentrated toafford a residue, which was purified using prep-TLC eluting withDCM/MeOH+ (10:1) to get benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)carbamate(88 mg, 53% yield) as an oil. MS (ESI) m/z 936.5 [M+H]⁺.

To a solution of benzyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)carbamate(88 mg, 0.094 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL).The mixture was stirred at RT for 1 h then concentrated, and the residuewas dissolved in DMF (2 mL) and adjusted to a pH of about 7 with TEA.The solvent was removed and the residue was purified using prep-HPLC aspreviously described to afford Compound 70 (19.9 mg, 27% yield) as asolid.

Example 71 Compound 71:4-((14-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 71 was prepared following similar procedure described inExamples 49 and 53.

Example 72 Compound 72:(S)-3-(4-((4-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Compound 72 was prepared following similar procedure described inExamples 8 and 53.

TABLE B Exemplary Compounds of Formulas (I) and (II) andCharacterization Data MS (ESI) m/z Chemical [M + ¹H NMR No. StructureH]⁺ (400 MHz, DMSO-d₆) 1

830.3 δ 10.96 (s, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.04 (s, 1H), 6.71(s, 1H), 6.50 (s, 1H), 6.06 (s, 1H), 4.97 (d, J = 9.2 Hz, 1H), 4.42 (s,2H), 4.35-4.18 (m, 2H), 4.05 (s, 2H), 3.08-2.83 (m, 9H), 2.60-2.50 (m,1H), 2.49-2.33 (m, 2H), 2.06- 2.00 (m, 3H), 1.73 (s, 4H), 1.40 (s, 4H),1.19-1.18 (m, 2H), 1.18 (s, 9H) 2

830.3 δ 12.24 (s, 1H), 10.98 (s, 1H), 7.83 (s, 1H), 7.73 (t, J = 5.2 Hz,1H), 7.38 (s, 1 H), 6.71 (s, 1H), 6.56 (t, J = 5.6 Hz, 1H), 6.10 (t, J =5.2 Hz, 1H), 5.01 (dd, J = 4.8, 12.8 Hz, 1H), 4.33 (d, J = 6.0 Hz, 2H),4.29-4.14 (m, 2H), 4.05 (s, 2H), 3.43-3.38 (m, 4H), 3.28-3.25 (m, 2H),3.18-3.15 (m, 2H), 2.93-2.81 (m, 5H), 2.61- 2.57 (m, 1H), 2.48-2.42 (m,1H), 2.35-2.24 (m, 1H), 2.09-1.97 (m, 3H), 1.73-1.69 (m, 4H), 1.17 (s,9H). 3

830.3 δ 12.23 (s, 1H), 10.94 (s, 1H), 7.74 (s, 1H), 7.38 (s, 1 H), 7.05(s, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 6.12 (s, 1H), 4.98 (dd, J = 3.6,12.4 Hz, 1H), 4.43 (d, J = 5.2 Hz, 2H), 4.35-4.18 (m, 2H), 4.05 (s, 2H),3.58-3.39 (m, 6H), 3.18 (d, J = 4.8 Hz, 2H), 2.91-2.82 (m, 5H),2.68-2.61 (m, 2H), 2.36-2.33 (m, 1H), 2.08-1.99 (m, 3H), 1.74-1.69 (m,4H), 1.17 (s, 9H). 4

793.4 δ 10.85 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.55(d, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.30 (t, J = 6.0 Hz, 1H), 5.89 (t, J= 5.6 Hz, 1H), 4.87 (dd, J = 4.8, 12.8 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 4.14-3.98 (m, 2H), 3.71 (s, 3H), 3.50 (s, 2H), 3.38-3.29 (m, 1H),2.91 (d, J = 6.0 Hz, 2H), 2.84-2.79 (m, 2H), 2.76-2.69 (m, 1H),2.45-2.41 (m, 1H), 2.17-2.11 (m, 1H), 1.86-1.81 (m, 3H), 1.76-1.63 (m,4H), 1.32-1.29 (m, 2H), 1.23-1.14 (m, 4H), 1.10- 1.02 (m, 6H), 0.84 (s,1H), 0.26 (s, 2H), 0.01 (s, 2H). 5

793.4 δ 10.79 (bs, 1H), 8.11 (s, 1H), 7.87 (bs, 1H), 7.53 (m, 1H), 7.03(bs, 1H), 6.90 (s, 1H), 6.34 (bs, 1H), 5.88 (bs, 1H), 4.83 (m, 1H), 4.27(m, 2H), 4.03 (m, 2H), 3.71 (m, 3H), 3.18 (m, 1H), 2.92 (m, 1H), 2.83(m, 4H), 2.69 (m, 1H), 2.35 (m, 1H), 1.87 (m, 3H), 1.85 (m, 4H), 1.77(m, 2H), 1.73 (m, 2H), 1.67-1.09 (m, 14H). 6

838.3 δ 12.15 (s, 1H), 10.72 (s, 1H), 7.73 (t, J = 5.6 Hz, 1H), 7.66 (d,J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.36 (d, J = 5.6 Hz, 1H),6.71 (s, 1H), 6.55 (t, J = 5.6 Hz, 1H), 6.07 (t, J = 5.6 Hz, 1H), 5.22(dd, J = 4.8, 12.4 Hz, 1H), 4.50 (s, 2H), 4.32 (d, J = 6.0 Hz, 2H), 4.04(s, 2H), 3.56-3.27 (m, 2H), 3.20-3.17 (m, 2H), 3.11-3.04 (m, 1H), 2.90(s, 2H), 2.82 (d, J = 11.6 Hz, 2H), 2.60-2.55 (m, 1H), 2.45-2.41 (m,1H), 2.28-2.23 (m, 1H), 2.12-1.99 (m, 4H), 1.84-1.81 (m, 1H), 1.73-1.68(m, 4H), 1.17 (s, 9H). 7

838.3 δ 10.91 (s, 1H), 7.72 (t, J = 6.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.48(s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.38 (s, 1 H), 6.71 (s, 1H), 5.25(dd, J = 4.8, 12.4 Hz, 1H), 4.54 (s, 2H), 4.30 (d, J = 6.0 Hz, 2H), 4.05(s, 2H), 3.44-3.37 (m, 2H), 3.19-3.14 (m, 2H), 3.13-3.05 (m, 1H), 2.89(s, 2H), 2.82 (d, J = 11.2 Hz, 2H), 2.61- 2.56 (m, 1H), 2.46-2.41 (m,1H), 2.33-2.24 (m, 1H), 2.12-2.03 (m, 4H), 1.88-1.79 (m, 1H), 1.74-1.68(m, 4H), 1.17 (s, 9H). 8

907.4 δ 10.96 (s, 1H), 8.27-8.25 (m, 2H), 8.01 (s, 1H), 7.66-7.54 (m,2H), 7.48-7.40 (m, 3H), 7.31-7.24 (m, 4H), 7.15 (s, 1H), 5.21 (s, 2H),5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.41-4.21 (m, 4H), 3.84 (s, 3H),3.64-3.45 (m, 2H), 3.10 (s, 2H), 3.05 (d, J = 6.4 Hz, 2H), 2.94-2.85 (m,1H), 2.58-2.49 (m, 1H), 2.43 (t, J = 6.8 Hz, 2H), 2.02-1.97 (m, 3H),1.90-1.87 (m, 2H), 1.80-1.77 (m, 3H), 1.47-1.44 (m, 2H), 1.37- 1.30 (m,3H), 1.27-1.19 (m, 7H), 0.98 (s, 1H), 0.39 (s, 2H), 0.13 (s, 2H). 9

801.4 δ 10.78 (s, 1H), 8.27 (s, 1H), 8.04-7.91 (m, 2H), 7.68 (d, J = 8.0Hz, 1H), 7.51-7.47 (m, 2H), 7.21 (s, 1H), 5.27 (dd, J = 4.8, 12.0 Hz,1H), 4.57-4.48 (m, 2H), 3.86 (s, 3H), 3.65- 3.35 (m, 4H), 3.13-3.06 (m,3H), 2.55-2.50 (m, 4H), 2.24-2.04 (m, 2H), 2.00-1.78 (m, 8H), 1.49-1.19(m, 13 H), 0.97 (s, 1H), 0.41 (s, 2H), 0.15 (s, 2H). 10

869.3 δ 12.25 (s, 1H), 11.11 (s, 1H), 7.72 (s, 1H), 7.58 (t, J = 8.0 Hz,1H), 7.38 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H),6.71 (s, 1H), 6.60 (t, J = 5.2 Hz, 1H), 5.05 (dd, J = 5.2, 12.4 Hz, 1H),4.05 (s, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.54-3.42 (m, 11H), 3.42-3.39(m, 2H), 3.27-3.22 (m, 2H), 2.93-2.81 (m, 5H), 2.61-2.54 (m, 1H),2.48-2.42 (m, 1H), 2.09- 1.99 (m, 3H), 1.73-1.68 (m, 4H), 1.17 (s, 9H).11

828.2 δ 12.20 (s, 1H), 10.97 (s, 1H), 7.82 (s, 1H), 7.69 (t, J = 5.6 Hz,1H), 7.34 (s, 1H), 6.71 (s, 1H), 6.43 (d, J = 5.2 Hz, 1H), 6.03 (t, J =4.8 Hz, 1H), 5.01 (dd, J = 8.4, 13.6 Hz, 1H), 4.33-4.14 (m, 4H), 4.05(s, 2H), 3.08-2.79 (m, 11H),2.61-2.56 (m, 1H), 2.32-2.26 (m, 1H),2.06-1.96 (m, 3H), 1.78-1.67 (m, 3H), 1.42-1.33 (m, 4H), 1.23-1.17 (m,11H). 12

800.2 δ 12.24 (s, 1H), 10.95 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 7.06(s, 1H), 6.71 (s, 1H), 6.63 (t, J = 5.2 Hz, 1H), 6.11 (t, J = 6.0 Hz,1H), 4.97 (dd, J = 8.4, 13.2 Hz, 1H), 4.43-4.17 (m, 4H), 4.05 (s, 2H),3.11-2.81 (m, 9H), 2.59- 2.55 (m, 1H), 2.35-2.31 (m, 1H), 2.09-1.97 (m,4H), 1.77-1.70 (m, 4H), 1.51-1.48 (m, 2H), 1.17 (s, 9H). 13

874.2 δ 12.22 (s, 1H), 10.95 (s, 1H), 7.73 (t, J = 5.6 Hz, 1H), 7.38 (s,1H), 7.05 (s, 1H), 6.71 (s, 1H), 6.66 (t, J = 6.0 Hz, 1H), 6.09 (t, J =5.6 Hz, 1H), 4.98 (dd, J = 5.2, 13.6 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H),4.34-4.17 (m, 2H), 4.04 (s, 2H), 3.51 (s, 4H), 3.44-3.34 (m, 4H), 3.27-3.23 (m, 2H), 3.19-3.15 (m, 2H), 2.92-2.80 (m, 5H), 2.59-2.55 (m, 1H),2.49-2.47 (m, 1H), 2.45-2.41 (m, 1H), 2.07-1.96 (m, 3H), 1.75-1.67 (m,4H), 1.17 (s, 9H). 14

828.2 δ 10.95 (s, 1H), 8.62 (s, 1H), 7.77 (s, 1H), 7.38 (s, 1H), 7.10(s, 1H), 6.71 (s, 1H), 5.00-4.96 (m, 2H), 4.53 (s, 2H), 4.36-4.18 (m,2H), 4.05 (s, 2H), 3.12-3.08 (m, 6H), 2.88-2.78 (m, 6H), 2.36-2.33 (m,1H), 2.24-2.06 (m, 4H), 1.73 (s, 4H), 1.41 (m, 5H), 1.24-1.18 (m, 11H).15

843.2 δ 12.20 (s, 1H), 10.95 (s, 1H), 7.68 (t, J = 5.6 Hz, 1H), 7.37 (s,1H), 7.04 (s, 1H), 6.71 (s, 1H), 6.65 (t, J = 5.6 Hz, 1H), 5.97 (t, J =5.6 Hz, 1H), 4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.60 (d, J = 4.4 Hz, 2H),4.34-4.17 (m, 2H), 4.04 (s, 2H), 3.20-3.15 (m, 2H), 3.11- 3.07 (m, 2H),2.91-2.81 (m, 5H), 2.58- 2.55 (m, 1H), 2.42-2.31 (m, 6H), 2.19 (s, 3H),2.07-1.96 (m, 4H), 1.73-1.68 (m, 4H), 1.37-1.23 (m, 1H), 1.17 (s, 9H).16

808.3 δ 10.94 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.76 (t, J = 5.2 Hz,1H), 7.16 (s, 1H), 7.04 (s, 1H), 6.50 (t, J = 5.2 Hz, 1H), 6.05 (t, J =5.6 Hz, 1H), 4.97 (dd, J = 4.8, 13.2 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H),4.35-4.17 (m, 2H), 3.86 (s, 3H), 3.67-3.60 (m, 1H), 3.08-2.97 (m, 8H),2.93-2.84 (m, 1H), 2.60-2.55 (m, 1H), 2.39-2.26 (m, 2H), 2.03-1.97 (m,1H), 1.90-1.81 (m, 4H), 1.43-1.35 (m, 4H), 1.32-1.24 (m, 5H), 1.12-0.97(m, 3H), 0.39 (s, 2H), 0.13 (s, 2H). 17

792.3 δ 10.94 (s, 1H), 8.23 (s, 1H), 7.84 (s, 1H), 7.76 (s, 1H), 7.04(s, 1H), 6.86 (s, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 4.97 (d, J = 8.8 Hz,1H), 4.42 (s, 2H), 4.34-4.17 (m, 2H), 3.86 (s, 3H), 3.64 (s, 1H),3.21-3.00 (m, 8H), 2.91-2.84 (m, 1H), 2.59-2.50 (m, 1H), 2.40-2.25 (m,2H), 2.07- 1.89 (m, 5H), 1.40-1.25 (m, 9H), 1.12-0.99 (m, 3H), 0.41 (s,2H), 0.23 (s, 2H). 18

856.3 δ 12.21 (s, 1H), 10.94 (s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.38 (s,1H), 7.04 (s, 1H), 6.71 (s, 1H), 6.48 (t, J = 6.0 Hz, 1H), 6.03 (t, J =5.6 Hz, 1H), 4.97 (dd, J = 8.4, 13.2 Hz, 1H), 4.42-4.17 (m, 4H), 4.05(s, 2H), 3.09-2.79 (m, 9H), 2.60-2.56 (m, 1H), 2.38-2.29 (m, 1H),2.11-1.96 (m, 4H), 1.74-1.66 (m, 4H), 1.46-1.33 (m, 4H), 1.29-1.23 (m,6H), 1.17 (s, 9H). 19

817.2 δ 10.94 (s, 1H), 7.37 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 6.65(t, J = 5.6 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 4.97 (dd, J = 6.4, 13.2Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 4.42-4.17 (m, 2H), 4.04 (s, 2H),3.50-3.48 (m, 8H), 3.19-3.15 (m, 2H), 2.91-2.84 (m, 3H), 2.60-2.55 (m,1H), 2.46-2.31 (m, 2H), 2.00-1.90 (m, 5H), 1.71-1.56 (m, 4H), 1.17 (s,9H). 20

813.2 δ 12.32 (s, 1H), 10.94 (s, 1H), 7.05 (s, 1H), 7.39 (s, 1H), 7.05(s, 1H), 6.72 (s, 1H), 6.53 (t, J = 5.6 Hz, 1H), 6.07 (t, J = 5.6 Hz,1H), 4.97 (dd, J = 8.4, 13.6 Hz, 1H), 8.42 (d, J = 5.6 Hz, 2H),4.35-4.17 (m, 2H), 4.05 (s, 2H), 3.02-2.84 (m, 5H), 2.60-2.55 (m, 2H),2.36-2.32 (m, 1H), 2.00-1.54 (m, 9H), 1.37-1.34 (m, 2H), 1.27-1.24 (m,10H), 1.18 (s, 9H). 21

749.3 δ 8.24 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 3.2 Hz, 1H), 7.04 (s,1H), 6.89 (s, 1H), 6.53 (s, 1H), 6.07 (s, 1H), 4.97 (dd, J = 4.4, 13.2Hz, 1H), 4.41 (d, J = 5.2 Hz, 2H), 4.34-4.18 (m, 2H), 3.86 (s, 3H),3.37-3.20 (m, 5H), 3.00-2.98 (m, 2H), 2.92-2.83 (m, 1H), 2.59-2.49 (m,1H), 2.35-2.29 (m, 2H), 1.99-1.89 (m, 5H), 1.37-1.25 (m, 10H), 1.12-1.06(m, 3H), 0.40 (d, J = 6.4 Hz, 2H), 0.23 (d, J = 3.2 Hz, 2H). 22

793.2 δ 8.25 (s, 1H), 8.01 (s, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 6.50 (t,J = 6.0 Hz, 1H), 6.03 (t, J = 5.6 Hz, 1H), 4.97 (dd, J = 4.8, 13.2 Hz,1H), 4.41 (d, J = 6.0 Hz, 2H), 4.35-4.17 (m, 2H), 3.85 (s, 3H),3.71-3.58 (m, 1H), 3.08-2.81 (m, 8H), 2.67-2.59 (m, 1H), 2.55-2.53 (m,2H), 2.42-2.28 (m, 3H), 2.01-1.89 (m, 3H), 1.38-1.33 (m, 4H), 1.30-1.25(m, 1H), 1.11- 0.96 (m, 3H), 0.39 (s, 2H), 0.13 (s, 2H). 23

776.9 δ 8.24 (d, J = 3.6 Hz, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.04 (s,1H), 6.86 (s, 1H), 6.51 (t, J = 6.0 Hz, 1H), 6.05 (t, J = 6.0 Hz, 1H),4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 4.35-4.17 (m,2H), 3.86 (s, 3H), 3.66-3.60 (m, 1H), 3.22-3.17 (m, 4H), 3.02-2.97 (m,2H), 2.89-2.85 (m, 1H), 2.67-2.59 (m, 1H), 2.54-2.50 (m, 2H), 2.39-2.32(m, 3H), 1.99- 1.97 (m, 1H), 1.92-1.89 (m, 4H), 1.38-1.26 (m, 14H),1.13-1.04 (m, 3H), 0.40 (d, J = 7.2 Hz, 2H), 0.22 (dd, J = 4.8, 9.6 Hz,2H). 24

765.2 δ 10.94 (s, 1H), 8.59 (br s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.25(s, 1H), 7.05 (s, 1H), 6.59 (t, J = 6.0 Hz, 1H), 6.14 (t, J = 5.6 Hz,1H), 4.97 (dd, J = 6.0, 13.6 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H),4.35-4.17 (m, 2H), 3.86 (s, 3H), 3.67-3.65 (m, 1H), 3.06-2.88 (m, 8H),2.67- 2.56 (m, 1H), 2.38-2.32 (m, 1H), 2.11-1.98 (m, 6H), 1.62-1.60 (m,2H), 1.39-1.23 (m, 15H), 0.98 (s, 1H), 0.87-0.84 (m, 1H), 0.41 (s, 2H),0.14 (s, 2H). 25

804.0 δ 10.95 (s, 1H), 8.51 (t, J = 5.2 Hz, 1H), 8.24 (d, J = 4.0 Hz,1H), 7.85 (d, J = 4.0 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.09 (s, 1H),6.89 (s, 1H), 4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H),4.35-4.18 (m, 2H), 3.86 (s, 3H), 3.68-3.63 (m, 1H), 3.21 (d, J = 6.4 Hz,2H), 3.11-3.07 (m, 6H), 2.92-2.83 (m, 1H), 2.59-2.55 (m, 2H), 2.45 (t, J= 6.8 Hz, 2H), 2.37-2.26 (m, 2H), 1.99-1.96 (m, 1H), 1.88- 1.85 (m, 4H),1.39-1.38 (m, 4H), 1.29-1.24 (m, 5H), 1.14-1.06 (m, 3H), 0.41 (d, J =7.2 Hz, 2H), 0.23 (d, J = 4.4 Hz, 2H). 26

888.2 δ 8.49 (t, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.71 (t, J = 5.6 Hz,1H), 7.38 (s, 1H), 6.71 (s, 1H), 5.00 (dd, J = 8.4, 13.6 Hz, 1H),4.43-4.15 (m, 4H), 4.05 (s, 2H), 3.49-3.15 (m, 12H), 2.89- 2.80 (m, 5H),2.63-2.56 (m, 3H), 2.46-2.29 (m, 2H), 2.09-1.95 (m, 3H), 1.77-1.68 (m,4H), 1.17 (s, 9H). 27

888.2 δ 8.49 (t, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.71 (t, J = 5.6 Hz,1H), 7.38 (s, 1H), 6.71 (s, 1H), 5.00 (dd, J = 8.4, 13.6 Hz, 1H),4.43-4.15 (m, 4H), 4.05 (s, 2H), 3.49-3.15 (m, 12H), 2.89- 2.80 (m, 5H),2.63-2.56 (m, 3H), 2.46-2.29 (m, 2H), 2.09-1.95 (m, 3H), 1.77-1.68 (m,4H), 1.17 (s, 9H). 28

925.2 δ 10.96 (s, 1 H), 8.27 (s, 3 H), 8.02 (br s, 1 H), 7.49-7.42 (m, 3H), 7.33-7.27 (m, 4 H), 7.21 (br s, 1 H), 5.21 (s, 1 H), 5.13-5.08 (m, 1H), 4.42-4.22 (m, 4 H), 3.96 (s, 2 H), 3.85 (s, 3 H), 3.62-3.57 (m, 6H), 3.49-3.44 (m, 4 H), 3.06- 3.04 (m, 2 H), 2.95-2.86 (m, 1 H),2.75-2.67 (m, 2 H), 2.43-2.40 (m, 1 H), 1.96 (s, 1 H), 1.31-1.26 (m, 4H), 0.98 (br s, 1 H), 0.41 (s, 2 H), 0.14 (s, 2 H). 29

792.3 δ 10.93 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.24 (d, J = 4.0 Hz,1H), 7.85 (d, J = 4.0 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.09 (s, 1H),6.86 (s, 1H), 4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H),4.35-4.18 (m, 2H), 3.86 (s, 3H), 3.68-3.63 (m, 1H), 3.21 (d, J = 6.4 Hz,4H), 3.12-3.09 (m, 7H), 2.92-2.83 (m, 1H), 2.67-2.55 (m, 1H), 2.45 (t, J= 6.8 Hz, 1H), 2.39-2.28 (m, 2H), 2.00-1.96 (m, 1H), 1.89- 1.86 (m,10H), 1.42 (s, 4H), 1.28-1.24 (m, 3H), 1.15-1.06 (m, 3H), 0.41 (d, J =7.6 Hz, 2H), 0.23 (d, J = 4.0 Hz, 2H). 30

822.3 δ 10.94 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.25 (s, 1H), 8.02 (s,1H), 7.74 (t, J = 5.6 Hz, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 4.97 (dd, J =5.2, 13.6 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 4.35- 4.18 (m, 2H), 3.85(s, 3H), 3.67-3.63 (m, 1H), 3.11-3.02 (m, 9H), 2.92-2.83 (m, 1H),2.67-2.58 (m, 1H), 2.47-2.43 (m, 3H), 2.36- 2.27 (m, 3H), 2.02-1.96 (m,2H), 1.90-1.80 (m, 4H), 1.46-1.39 (m, 4H), 1.31-1.27 (m, 2H), 1.12-0.96(m, 3H), 0.39 (s, 2H), 0.13 (s, 2H). 31

822.3 δ 10.99 (s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.02 (s,1 H), 7.85 (s, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.18 (s, 1H), 5.00 (dd, J= 4.8, 13.2 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.30- 4.15 (m, 2H), 3.85(s, 3H), 3.66-3.61 (m, 2H), 3.10-3.04 (m, 8H), 2.93-2.84 (m, 1H),2.60-2.54 (m, 1H), 2.43 (t, J = 6.8 Hz, 2H), 2.36-2.25 (m, 2H),2.02-1.95 (m, 2H), 1.89- 1.85 (m, 4H), 1.47-1.35 (m, 4H), 1.31-1.22 (m,4 H), 1.11-0.97 (m, 3H), 0.39 (s, 2 H), 0.13 (s, 2H). 32

δ 10.92 (s, 1H), 8.46 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 3.6 Hz, 1H),7.85 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.75 (t, J = 6.4 Hz, 1H), 6.88(s, 1H), 5.01 (dd, J = 5.2, 12.0 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H),4.30-4.15 (m, 2H), 3.66 (s, 3H), 3.64-3.59 (m, 1H), 3.21 (d, J = 6.4 Hz,2H), 3.10-3.05 (m, 6H), 2.93-2.84 (m, 1H), 2.60-2.56 (m, 1H), 2.43 (t, J= 7.2 Hz, 2H), 2.33-2.27 (m, 2H), 1.98-1.96 (m, 1H), 1.89- 1.85 (m, 4H),1.43-1.36 (m, 4H), 1.29-1.21 (m, 5H), 1.15-1.06 (m, 3H), 0.40 (d, J =7.2 Hz, 2H), 0.23 (dd, J = 4.8, 10.0 Hz, 2H). 33

842.2 δ 10.97 (s, 1H), 8.46 (t, J = 5.6 Hz, 1H), 7.85 (s, 1H), 7.69 (t,J = 5.6 Hz, 1H), 7.38 (s, 1H), 6.71 (s, 1H), 5.01 (dd, J = 8.0, 13.6 Hz,1H), 4.41 (d, J = 5.6 Hz, 2H), 4.31-4.15 (m, 2H), 4.05 (s, 2H),3.11-3.04 (m, 4H), 2.87-2.79 (m, 5H), 2.60-2.55 (m, 2H), 2.46-2.42 (m,2H), 2.33-2.29 (m, 1H), 2.09-1.96 (m, 4H), 1.76-1.69 (m, 4H), 1.46-1.36(m, 4H), 1.17 (s, 9H). 34

888.7 δ 8.56 (t, J = 6.0 Hz, 1H), 7.72 (t, J = 6.4 Hz, 1H), 7.38 (s,1H), 7.09 (s, 1H), 6.71 (s, 1H), 4.98 (dd, J = 8.0, 13.6 Hz, 1H), 4.53-4.18 (m, 4H), 4.05 (s, 2H), 3.49-3.16 (m, 12H), 2.87-2.80 (m, 5H),2.64-2.55 (m, 3H), 2.45-2.41 (m, 1H), 2.36-2.32 (m, 1H), 2.08-1.96 (m,3H), 1.76-1.66 (m, 4H), 1.17 (s, 9H). 35

808.3 δ 10.80 (s, 1H), 8.41 (t, J = 5.6 Hz, 1H), 8.12 (d, J = 3.6 Hz,1H), 7.85 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.75 (t, J = 6.4 Hz, 1H),6.88 (s, 1H), 5.01 (dd, J = 5.2, 12.0 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H),4.30-4.15 (m, 2H), 3.66 (s, 3H), 3.64-3.59 (m, 1H), 3.21 (d, J = 6.4 Hz,2H), 3.10-3.05 (m, 6H), 2.93-2.84 (m, 1H), 2.60-2.56 (m, 1H), 2.43 (t, J= 7.2 Hz, 2H), 2.33-2.27 (m, 2H), 1.98-1.96 (m, 1H), 1.89- 1.85 (m, 4H),1.43-1.36 (m, 4H), 1.29-1.21 (m, 5H), 1.15-1.06 (m, 3H), 0.72 (d, J =7.2 Hz, 2H), 0.70 (dd, J = 4.8, 10.0 Hz, 2H). 36

822.2 δ 11.01 (s, 1H), 9.31 (t, J = 6.0 Hz, 1H), 8.87-8.86 (m, 4H), 8.49(t, J = 5.2 Hz, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 7.27-7.24(m, 1H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H),4.56-4.53 (m, 1H), 3.86 (s, 3H), 3.17-3.12 (m, 2H), 3.04 (d, J = 6.4 Hz,4H), 2.91-2.83 (m, 1H), 2.67-2.51 (m, 1H), 2.83-2.32 (m, 1H), 2.06-1.98(m, 6H), 1.65-1.58 (m, 2H), 1.50-1.24 (m, 7H), 0.99 (s, 1H), 0.43 (s,2H), 0.16 (s, 2H). 37

806.2 δ 11.09 (s, 1H), 9.27 (t, J = 6.0 Hz, 1H), 8.84 (s, 1H), 8.46 (t,J = 6.0 Hz, 1H), 8.27 (d, J = 3.6 Hz, 1H), 7.86 (d, J = 4.4 Hz, 1H),7.45 (s, 1H), 6.98 (s, 1H), 5.03 (dd, J = 7.6, 13.2 Hz, 1H), 4.66 (d, J= 5.6 Hz, 2H), 3.87 (s, 3H), 3.82-3.80 (m, 1H), 3.72-3.70 (m, 1H), 3.64(s, 1H), 3.20-3.15 (m, 4H), 3.03-2.94 (m, 3H), 2.88-2.83 (m, 2H),2.67-2.49 (m, 1H), 2.07-2.01 (m, 4H), 1.65-1.59 (m, 2H), 1.49- 1.44 (m,5H), 1.34-1.06 (m, 7H), 0.42 (d, J = 7.6 Hz, 2H), 0.25 (d, J = 4.8 Hz,2H). 38

808.3 δ 10.83 (s, 1H), 8.35 (t, J = 5.2 Hz, 1H), 8.33 (d, J = 4.0 Hz,1H), 8.12 (d, J = 4.0 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.09 (s, 1H),6.89 (s, 1H), 4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H),4.35-4.18 (m, 2H), 3.86 (s, 3H), 3.68-3.63 (m, 1H), 3.21 (d, J = 6.4 Hz,2H), 3.11-3.07 (m, 6H), 2.92-2.83 (m, 1H), 2.59-2.55 (m, 2H), 2.45 (t, J= 6.8 Hz, 2H), 2.37-2.26 (m, 2H), 1.99-1.96 (m, 1H), 1.88- 1.85 (m, 4H),1.39-1.38 (m, 4H), 1.29-1.24 (m, 5H), 1.14-1.06 (m, 3H), 0.41 (d, J =7.2 Hz, 2H), 0.23 (d, J = 4.4 Hz, 2H). 39

792.4 δ 10.96 (s, 1H), 8.48 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 4.0 Hz,1H), 7.85-7.84 (m, 2H), 7.78 (t, J = 5.2 Hz, 1H), 6.86 (s, 1H), 5.01(dd, J = 5.2, 13.2 Hz, 1H), 4.42 (d, J = 5.6 Hz, 2H), 4.30- 4.15 (m,2H), 3.86 (s, 3H), 3.64 (s, 1H), 3.21 (d, J = 6.8 Hz, 2H), 3.11-3.07 (m,6H), 2.61- 2.56 (m, 1H), 2.49-2.44 (m, 1H), 2.32-2.30 (m, 2H), 1.98-1.86(m, 10H), 1.41 (s, 4H), 1.31-1.22 (m, 2H), 1.15-1.06 (m, 3H), 0.40 (d, J= 7.2 Hz, 2H), 0.23 (d, J = 4.0 Hz, 2H). 40

780.3 δ 10.93 (s, 1H), 8.56 (t, J = 6.4 Hz, 1H), 8.25 (s, 1H), 8.00 (s,1H), 7.82 (t, J = 6.0 Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 4.97 (dd, J =5.2, 13.6 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 4.34- 4.17 (m, 2H), 3.85(s, 3H), 3.85-3.65 (m, 1H), 3.18-3.15 (m, 5H), 3.14-3.05 (m, 4H),2.92-2.82 (m, 1H), 2.67-2.66 (m, 3H), 2.35- 2.28 (m, 3H), 2.00-1.97 (m,1H), 1.90-1.85 (m, 8H), 1.23-1.23 (m, 3H), 1.23-0.97 (m, 4H), 0.39 (s,2H), 0.13 (s, 2H). 41

932.2 δ 12.22 (s, 1H), 11.07 (s, 1H), 7.69 (s, 1H), 7.38 (s, 1H), 7.32(s, 1H), 6.71 (s, 1H), 6.61 (t, J = 5.6 Hz, 1H), 6.15 (t, J = 5.6 Hz,1H), 5.02 (dd, J = 5.6, 13.2 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.05 (s,2H), 3.29-2.78 (m, 4H), 2.67-2.51 (m, 5H), 2.49-2.32 (m, 1H), 2.09- 1.91(m, 3H), 2.28-2.02 (m, 2H), 1.84-1.73 (m, 4H), 1.43-1.38 (m, 4H),1.26-1.21 (m, 2H), 1.17 (s, 9H). 42

932.2 δ 8.56 (t, J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.38 (s,1H), 7.09 (s, 1H), 6.71 (s, 1H), 4.98 (dd, J = 6.8, 17.6 Hz, 1H), 4.52(d, J = 8.0 Hz, 2H), 4.36-4.17 (m, 2H), 4.05 (s, 2H), 3.29- 2.78 (m,4H), 2.67-2.51 (m, 5H), 2.49- 2.32 (m, 1H), 2.09-1.91 (m, 3H), 2.28-2.02 (m, 2H), 1.84-1.73 (m, 4H), 1.43-1.38 (m, 4H), 1.26-1.21 (m, 2H),1.17 (s, 9H). 43

912.5 δ 10.93 (s, 1H), 8.54 (t, J = 6.8 Hz, 1H), 8.25 (s, 1H), 8.00 (s,1H), 7.82 (t, J = 5.6 Hz, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 4.97 (dd, J =4.8, 13.2 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 4.35- 4.17 (m, 2H), 3.87(s, 3H), 3.50 (s, 1H), 3.50-3.44 (m, 7H), 3.40-3.31 (m, 5H), 3.25- 3.22(m, 3H), 3.15-3.06 (m, 6H), 2.89- 2.87 (m, 1H), 2.67-2.55 (m, 3H),2.33-2.31 (m, 3H), 1.99-1.98 (m, 2H), 1.31-1.23 (m, 5H), 0.98(s, 2H),0.38 (s, 2H), 0.12 (s, 2H). 44

856.2 δ 12.44 (s, 1H), 11.00 (s, 1H), 9.16 (s, 1H), 8.73 (br s, 1H),7.93 (s, 1H), 7.41 (s, 1H), 6.72 (s, 1H), 5.03 (dd, J = 5.2, 13.2 Hz,1H), 4.51 (d, J = 5.6 Hz, 2H), 4.38-4.18 (m, 2H), 4.07 (s, 2H), 3.92 (s,2H), 3.83 (s, 2H), 3.26-3.17 (m, 4H), 3.13-3.10 (m, 4H), 2.98-2.87 (m,1H), 2.76 (s, 1H), 2.75-2.58 (m, 3H), 2.38- 2.67 (m, 1H), 2.02-1.96 (m,5H), 1.49-1.44 (m, 5H), 1.24 (s, 1H), 1.19 (s, 9H). 45

766.3 δ 10.96 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz,1H), 7.01 (s, 1H), 6.68 (t, J = 6.4 Hz, 1H), 6.17 (d, J = 5.2 Hz, 1H),4.96 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 4.33- 4.16(m, 2H), 3.84 (s, 3H), 3.65-3.63 (m, 1H), 3.12-3.08 (m, 8H), 2.89-2.87(m, 1H), 2.37-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.28-1.23 (m, 3H),1.17-1.03 (m, 2H), 0.38 (s, 2H), 0.12 (s, 2H). 46

898.4 δ 10.93 (s, 1H), 8.25 (s, 1H), 8.01-7.07 (m, 2H), 7.17 (d, J = 7.2Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 6.65-6.62 (m, 1H), 6.08 (t, J = 5.6Hz, 1H), 4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.42 (d, J = 5.6 Hz, 2H),4.34-4.16 (m, 2H), 3.85- 3.83 (m, 3H), 3.64 (s, 1H), 3.50-3.44 (m, 8H),3.42-3.37 (m, 5H), 3.27-3.24 (m, 3H), 3.17-3.13 (m, 4H), 3.07-3.04 (m,2H), 2.92- 2.84 (m, 1H), 1.98-1.97 (m, 2H), 1.29-1.23 (m, 6H), 1.10-1.07(m, 2H), 0.87-0.84 (m, 1H), 0.39 (s, 2H), 0.13 (s, 2H). 47

856.2 δ 10.96 (s, 1H), 9.20 (s, 1H), 7.92 (s, 1H), 7.37 (s, 1H), 7.15(s, 1H), 6.71 (s, 1H), 4.98 (d, J = 17.2 Hz, 1H), 4.55 (d, J = 5.2 Hz,2H), 4.37-4.18 (m, 2H), 4.05 (s, 2H), 3.52 (s, 2H), 3.26 (s, 3H),2.93-2.85 (m, 6H), 2.68 (s, 2H), 2.31 (m, 5H), 2.08-1.91 (m, 4H), 1.74(s, 4H), 1.23 (s, 2H), 1.17 (s, 9H). 48

806.3 δ 11.09 (s, 1H), 8.72 (s, 1H), 8.24 (t, J = 3.6 Hz, 1H), 7.84 (t,J = 4.4 Hz, 1H), 6.86 (s, 1H), 5.04 (dd, J = 5.6, 12.8 Hz, 1H), 4.67 (d,J = 4.8 Hz, 2H), 3.86 (s, 3H), 3.66-3.59 (m, 1H), 3.24-3.04 (m, 10H),2.92-2.83 (m, 1H), 2.68-2.67 (m, 1H), 2.35-2.32 (m, 1H), 2.04-2.00 (m,1H), 1.93-1.87 (m, 10H), 1.43 (s, 4H), 1.31-1.02 (m, 6H), 0.41 (d, J =8.8 Hz, 2H), 0.23 (d, J = 4.8 Hz, 2H). 49

849.3 δ 11.07 (s, 1H), 8.25 (s, 1H), 8.00-7.85 (m, 2H), 7.57 (t, J = 8.0Hz, 1H), 7.14-7.03 (m, 3H), 6.59 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 7.6,12.8 Hz, 1H), 3.85 (s, 3H), 3.62-3.39 (m, 16H), 3.26 (s, 2H), 3.26-3.24(m, 2H), 3.11-3.06 (m, 4H), 2.93-2.83 (m, 1H), 2.60- 2.56 (m, 1H), 2.32(s, 1H), 2.03-1.97 (m, 1H), 1.91-1.81 (m, 3H), 1.11-0.97 (m, 3H),0.39-0.38 (m, 2H), 0.13-0.12 (m, 2H). 50

833.3 δ 10.87 (s, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.61-7.60 (m, 2H), 7.34(t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 6.8 Hz, 1H),6.65 (s, 1H), 6.36 (t, J = 5.6 Hz, 1H), 4.81 (dd, J = 7.6, 12.8 Hz, 1H),3.62 (s, 3H), 3.36-3.16 (m, 15H), 3.03-2.96 (m, 4H), 2.88 (s, 2H),2.69-2.60 (m, 1H), 2.33-2.30 (m, 1H), 2.09- 2.04 (m, 1H), 1.80-1.77 (m,1H), 1.67-1.62 (m, 4H), 1.06-0.77 (m, 5H), 0.18-0.16 (m, 2H), 0.01-0 (m,2H). 51

822.2 δ 11.11 (s, 1H), 8.71-8.69 (m, 1H), 8.25- 8.23 (m, 2H), 8.04-8.00(m, 1H), 7.79-7.76 (m, 1H), 7.19-7.17 (m, 1H), 5.04 (dd, J = 4.8, 12.0Hz, 1H), 4.67 (d, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.69-3.62 (m, 1H), 3.16(s, 2H), 3.08 (s, 6H), 3.88-2.82 (m, 1H), 2.67-2.58 (m, 1H), 1.90-1.86(m, 10H), 1.42 (s, 4H), 1.31- 1.23 (m, 2H), 1.12-0.94 (m, 3H), 0.39 (d,J = 4.0 Hz, 2H), 0.12 (d, J = 1.6 Hz, 2H). 52

814.1 δ 10.95 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 7.78 (t, J = 5.2 Hz,1H), 7.38 (s, 1H), 7.09 (s, 1H), 6.71 (s, 1H), 4.97 (t, J = 5.6 Hz, 1H),4.97 (dd, J = 5.2, 13.2 Hz, 1H), 4.54-4.49 (m, 1H), 4.36-4.16 (m, 2H),4.05 (m, 2H), 3.28-3.12 (m, 6H), 2.91-2.82 (m, 4H), 2.08-2.03 (m, 2H),1.89-1.78 (m, 3H), 1.72-1.69 (m, 3H), 1.59- 1.58 (m, 1H), 1.24-1.17 (m,7H). 53

793.3 δ 8.49 (t, J = 6.0 Hz, 1 H), 8.25 (s, 1 H), 8.01 (brs, 1 H), 7.13(brs, 1 H), 7.09 (s, 1 H), 4.97 (dd, J = 4.8, 13.2 Hz, 1 H), 4.52 (d, J= 6.0 Hz, 2 H), 4.35-4.17 (m, 2 H), 3.85 (s, 3 H), 3.65- 3.64 (m, 2 H),3.10-3.07 (m, 4 H), 2.90- 2.84 (m, 1 H), 2.60-2.58 (m, 1 H), 2.46-2.39(m, 3 H), 2.36-2.32 (m, 3 H), 1.99-1.96 (m, 1 H), 1.90-1.87 (m, 11 H),1.36-1.31 (m, 4 H), 1.29-1.25 (m, 2 H), 1.10-0.97 (m, 3 H), 0.39-0.38(m, 2 H), 0.14-0.12 (m, 2 H). 54

877.2 55

835.3 56

819.3 57

813.2 58

919.2 59

776.3 60

765.3 [M + H]⁺ 61

820.4 δ 8.25 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.17-7.15 (m, 1H),6.44-6.40 (m, 1H), 5.95 (t, J = 5.6 Hz, 1H), 5.84-5.80 (m, 1H), 5.15(dd, J = 5.6, 11.2 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H),3.65-3.60 (m, 3H), 3.08-3.06 (m, 3H), 2.99-2.98 (m, 3H), 2.83-2.81 (m,1H), 2.67-2.66 (m, 1H), 2.55 (s, 3H), 2.33- 2.32 (m, 1H), 2.14-2.09 (m,1H), 1.90-1.88 (m, 4H), 1.36-1.34 (m, 4H), 1.24 (s, 12H), 1.10-1.04 (m,1H), 0.39-0.37 (m, 2H), 0.12- 0.11 (m, 2H). 62

839.3 63

763.3 64

836.3 65

760.3 66

798.2 67

860.3 δ 8.25 (s, 1H), 8.00 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.16 (s,1H), 6.95 (d, J = 8.4 Hz, 2H), 5.27 (s, 2H), 5.02 (dd, J = 5.2, 13.2 Hz,1H), 4.36-4.20 (m, 2H), 3.85 (s, 3H), 3.64 (s, 3H), 3.49-3.43 (m, 10 H),3.07 (d, J = 5.6 Hz, 2H), 2.93-2.84 (m, 1H), 2.67 (t, J = 5.2 Hz, 2H),2.62 (t, J = 5.6 Hz, 2H), 2.57-2.55 (m, 1H), 2.39-2.31 (m, 2H),1.99-1.97 (m, 1H), 1.90- 1.87 (m, 3H), 1.34-1.24 (m, 3H), 1.06-0.97 (m,3H), 0.39 (s, 2H), 0.12 (s, 2H). 68

842.3 69

904.3 70

802.3 δ 8.25 (s, 1H), 8.01 (s, 1H), 7.40-7.33 (m, 2H), 7.15 (d, J = 5.6Hz, 1H), 5.15 (dd, J = 4.8 Hz, 13.2 Hz, 2H), 4.52 (dd, J = 17.2, 67.2Hz, 1H), 3.85 (s, 3H), 3.15- 3.068 (m, 2H), 2.96-2.88 (m, 3H), 2.61-2.53(m, 4H), 2.44-2.38 (m, 2H), 2.28-2.25 (m, 2H), 2.06-1.98 (m, 8H),1.90-1.72 (m, 4H), 1.42-1.27 (m, 4H), 1.27- 1.13 (m, 8H), 1.10-1.07 (m,2H), 0.97 (s, 1H), 0.39 (s, 2H), 0.12 (s, 2H). 71

836.3 72

899.0

Biological Assays

Western Blot Analysis

MV-4-11 cells were grown in RPMI 1640 media supplemented with 10% fetalbovine serum, streptomycin and penicillin.

Cells were cultured at approximately 10⁶ cells per mL and incubated inDMSO or the indicated compound for 6-8 h. Whole cell extracts wereprepared using RIPA buffer according to manufacturer's protocol(Pierce). Briefly, 3×10⁶ cells were washed once in PBS, the cell pelletswere resuspended in RIPA buffer and allowed to incubate for 15 minuteson ice. Cells debris was removed by centrifugation and the cleared wholecell lysates were transferred to new tubes for further analysis.

For Western blot analysis, whole cell protein extracts were separated on4-12% SDS-polyacrylamide gels, transferred to nitrocellulose and probedwith the indicated primary antibodies. Membranes were subsequentlywashed and probed with the appropriate IRDye secondary antibodies(LI-COR). The signal was detected using the Odyssey Imaging System(LI-COR).

The following antibodies were used in these studies: Anti-eRF3/GSPT1:Abcam, ab126090 (Cambridge, Mass.); Anti-Ikaros: Abcam, ab191394(Cambridge, Mass.); Anti-CK1α: Abcam, ab108296 (Cambridge, Mass.);Anti-CDK9: Santa Cruz Biotechnology, sc13130 (Dallas, Tex.); Anti-CDK16:Millipore Sigma, HPA001366 (St. Louis, Mo.); 3-actin (8H10comD10) mousemonoclonal antibody: Cell Signaling Technology, #3700 (Danvers, Mass.);IRDye 680RD Goat anti-rabbit antibody: LI-COR, 926-68071 (Lincoln,Nebr.); IRDye 800CW Goat anti-mouse antibody: LI-COR, 926-32210(Lincoln, Nebr.).

IKAROS activities are shown in Table 1. CK1α activities are shown inTable 2. GSPT1 activities are shown in Table 3. CDK9 activities areshown in Table 4 at two different concentrations. CDK16 activities areshown in Table 5 at two different concentrations. In each of Tables 1-5,the % degradation values are reported as “A”, “B”, “C”, or “D”. “A”represents a % degradation value of less than 25% (value <25%). “B”represents a % degradation value of equal to or more than 25% and lessthan 50% (25%≤value<50%). “C” represents a % degradation value of equalto or more than 50% and less than 75% (50%≤value<75%). “D” represents a% degradation value of equal to or more than 75% (value ≥75%).

TABLE 1 Activity of Compounds in IKAROS degradation assay. Compoundstested at 1 μM. Compound IKAROS No. % Degradation at 1 μM 2 B 6 B 7 A 8C 10 C 14 A 18 B 20 C 21 D 24 B 25 B 26 C 27 B 28 C 29 C 30 C 32 C 33 C34 C 35 C 37 B 38 B 39 B 40 C 41 C 42 B 45 B 49 C 50 D 51 C 52 B 54 C 55D 56 C 57 B 58 A 61 B 63 B 64 D 67 B 68 D 69 D

TABLE 2 Activity of Compounds in CK1α degradation assay. Compoundstested at 1 μM. Compound CK1α No. % Degradation at 1 μM 3 B 6 A 7 A 9 A11 B 18 C 22 A 30 A 33 D 34 B 35 B 37 B 39 B 40 B 41 C 45 A 50 B 51 B 52B 54 C 55 B 56 B 58 D 64 B 65 C 67 B 69 C

TABLE 3 Activity of Compounds in GSPT1 degradation assay. Compoundstested at 1 μM. Compound GSPT1 No. % Degradation at 1 μM 4 B 8 A 9 C 11B 14 B 18 C 28 A 29 A 30 C 32 B 33 D 34 C 35 D 37 C 38 C 39 C 40 D 41 D43 C 45 B 49 A 50 C 51 B 52 C 55 C 63 A 64 D 65 B 66 C 67 C 68 D

TABLE 4 Activity of Compounds in CDK9 degradation assay. Compoundstested at 0.1 μM and 1 μM. Compound CDK9 CDK9 No. % Degradation at 0.1μM % Degradation at 1 μM 12 D D 13 C D 14 B D 15 C D 16 C D 17 C D 22 CD 23 D D 24 C D 25 C C 26 C D 29 B C 30 C C 31 B D 32 C D 33 D D 34 A D35 B B 36 A B 38 C D 39 B D 40 C D 41 C D 42 B D

TABLE 5 Activity of Compounds in CDK16 degradation assay. Compoundstested at 0.1 μM and 1 μM. Compound CDK16 CDK16 No. % Degradation at 0.1μM % Degradation at 1 μM 12 B B 13 A A 14 A B 15 A A 16 D D 17 C C 22 AC 23 C D 24 C D 25 c C 26 B A 29 B C 30 B C 31 B D 32 C D 33 A C 34 B A35 A C 36 A B 38 C D 39 A D 40 B C 41 A A 42 A A

Cell-Based Assay

Either frozen primary blood mononuclear cells (PBMCs) or frozen CD14+mobilized peripheral blood monocytes were purchased from AllCells(PB003F, Normal Peripheral Blood MNC (Alameda, Calif.)). Cells werequick thawed, washed 1-time with RPMI-1640 (10% FBS/1% Pen-Strep) andplated in 96 well plates at 200,000 cells per well. Cells werepretreated with DMSO only or with the indicated compound for 1 h andthen induced with 100 ng/mL lipopolysaccharide (LPS) for 18-24 h. Thesupernatant was analyzed for IL-1β, IL-6, and TNFα, using Meso Scaleassay according to manufacturer's protocol. The negative control wellswere treated with DMSO.

For the IL-2 analysis, 96 well plates were precoated with 1 μg/mLanti-human CD3 antibody (OK3, eBioscience Inc., San Diego, Calif.).After washing with PBS, the indicated compound was added (50 μL/well)followed by PBMCs diluted at 3-4 million cells/mL (150 μL/well). Plateswere incubated for 24 h and the supernatants collected for MesoscaleIL-2 analysis. IL-2 activity is measured as fold difference from theDMSO control.

IL-1β, IL-6, and TNFα activities are shown in Table 6. IL-2 activitiesare shown in Table 7. In Table 6, the % inhibition values are reportedas “A”, “B”, “C”, or “D”. “A” represents a % inhibition value of lessthan 50% (value <50%). “B” represents a % inhibition value of equal toor more than 50% and less than 70% (50%≤value<70%). “C” represents a %inhibition value of equal to or more than 70% and less than 90%(70%≤value<90%). “D” represents a % inhibition value of equal or morethan 90% (value ≥90%). In Table 7, the fold-change values are reportedas “A”, “B”, “C”, or “D”. “A” represents a fold-change value of equal toor less than 0.1 (value ≤0.1). “B” represents a fold-change value ofmore than 0.1 and equal to or less than 0.5 (0.1<value≤0.5). “C”represents a fold-change value of more than 0.5 and equal to or lessthan 1 (0.5<value≤1). “D” represents a fold-change value of more than 1(value >1).

TABLE 6 Activity of Compounds in IL-1β, IL-6, and TNF-α inhibitionassays. Compounds tested at 1 μM. IL-1β IL-6 TNF-α Compound % Inhibition% Inhibition % Inhibition No. at 1 μM at 1 μM at 1 μM 2 D D C 3 D D C 5D D c 6 A B A 7 A A A 8 A A A 9 B A B 13 D D D 18 D D C 19 D D C 21 A AA 26 D D C 28 D D D 34 C C C 36 C C C 37 D D C 41 D D C 42 D D A 43 A AA 44 B A B 46 C C B 51 D D D 55 D D D 56 D D D 57 D D D 58 D C A 59 C CA 61 D D D 65 A A A 66 A A A 67 D D D 69 C A C

TABLE 7 Activity of Compounds in IL-2 fold-change assay. Compoundstested at 1 μM. Compound IL-2 Fold-Change No. at 1 μM 2 B 3 B 9 C 13 A18 A 21 B 26 A 28 A 34 A 37 B 41 B 42 B 46 B 51 A 55 A 56 A 57 A 58 C 59C 61 B 63 D 65 C 67 C

Cell Viability Assay

MOLM-13 cells were cultured in RPMI 1640 media supplemented with 10%fetal bovine serum, streptomycin and penicillin, and were plated inwalled 96-well plates at 2500 cells/well. Cells were incubated in DMSO(control) or the indicated compound for 3 days at 37° C. and 5% CO₂.Following the incubation period, 100 μL of CellTiterGlow (CTG) reagent(CellTiter-Glo® Luminescent Cell Viability Assay, Promega (Madison,Wis.)) was added to each well. Following a 10 minutes incubation withshaking, luminescence was measured using the EnVision Multimode platereader.

Antiproliferative activities of compounds in MOLM-13 cell viabilityassay are shown in Table 8. The MOLM-13 cell viability values as % DMSOare reported as “A”, “B”, “C”, or “D”. “A” represents a % viabilityvalue of less than 50% (value <50%). “B” represents a % viability valueof equal to or more than 50% and less than 70% (50%≤value<70%). “C”represents a % viability value of equal to or more than 70% and lessthan 90% (70%≤value<90%). “D” represents a % viability value of equal ormore than 90% (value ≥90%). The results indicated that the compoundsinhibited cancer cell viability, such as leukemia cell viability.

TABLE 8 Activity of Compounds in MOLM-13 cell viability assays.Compounds tested at 1 μM. Compound MOLM-13 Cell Viability No. % DMSO at1 μM 1 D 2 D 3 D 4 D 5 D 6 A 7 A 8 C 9 A 11 D 12 D 13 D 14 D 15 C 16 D18 D 19 C 20 D 21 D 22 D 23 D 24 D 25 D 26 D 27 D 28 D 29 D 30 D 31 D 32D 33 D 34 D 35 D 36 B 37 B 38 D 39 D 40 C 41 C 42 C 43 B 44 B 45 D 46 D47 C 48 D 49 D 50 D 51 D 52 D 53 D 54 D 55 D 56 D 57 D 58 B 59 D 60 D 61D 62 D 63 D 64 D 65 A 66 B 67 D 68 D 69 A

What is claimed is:
 1. A compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein: R¹ is

wherein R¹ is optionally substituted with one or more R^(A); n is 1, 2,or 3; each R^(2a) and R^(2b) is independently H, deuterium, halogen, orC₁-C₆ alkyl; each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R^(A) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino,C₁-C₆ alkylamino, amino(C₁-C₆ alkyl), —(C═O)NR^(10a)R^(10b) (C₁-C₆alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionallysubstituted C₃-C₇ cycloalkyl; each of R⁴, R⁵ and R⁶ is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,optionally substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl), or optionallysubstituted C₃-C₇ cycloalkyl; each of R^(7a) and R^(7b) is independentlyH, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; eachof R^(8a) and R^(8b) is independently H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; each ofR^(9a) and R^(9b) is independently H, optionally substituted C₁-C₆alkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(10a) andR^(10b) is independently H or C₁-C₆ alkyl, or R^(10a) and R^(10b)together with the nitrogen atom to which they are attached form anoptionally substituted 5 or 6 membered heterocyclyl optionallysubstituted with one or more R¹¹; each R¹¹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted amino,halogen, or cyano; or two geminal R¹¹ form oxo; Q is CH₂ or C═O; L¹ is abond,

*—Z^(1e)-Z³—(CH₂)_(m5)—,

wherein the asterisk * indicates the point of connection to X¹; each ofZ^(1a), Z^(1b), Z^(1c), Z^(1d), Z^(1e), and Z^(1f) is independently abond or —(CR^(a)R^(b))_(q1)—; Z² is —(CR^(c)R^(d))_(q2)—; Z³ is a bond,O or NR^(12g); each of R^(a), R^(b), R^(c) and R^(d) is independently H,halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl; each q1 and q2is independently 1, 2 or 3; each X^(a) and X^(b) is independently O orS; each Ring A is independently phenyl or a five to six memberedheteroaryl, each optionally substituted with one or more R¹¹; each ofY¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is —NR^(12h)—, —O—, or —S—; each R^(12a),R^(12b), R^(12c), R^(12d), R^(12e), R^(12f), R^(12g) and R^(12h) isindependently H or C₁-C₆ alkyl; each of m1, m2, m3, m4, m5, m6, k1, k2,k3, k4, k5, k6, p1, p2, p3, p4, p5, and p6 is independently 0, 1, 2, or3; L² is a bond, —C(═O)—, or —(CH₂)₀₋₃—C(═O)NR³—; R¹³ is H or C₁-C₆alkyl; X¹ is C₁-C₁₅ alkylene or heteroalkylene; X² is —NHC(═O)—, —NH—,—O—, —NHC(═O)NH—, —NHCH₂— or —S—; and X³ is —NH—, —O—, or —S—; providedthat when the compound has the structure

R¹ is

Q is C═O, n is 2, R³ is H, then R^(2a) is deuterium, halogen, or C₁-C₆alkyl.
 2. The compound of claim 1, wherein R¹ is


3. The compound of claim 1 or 2, wherein R^(2a) is H.
 4. The compound ofany one of claims 1 to 3, wherein R^(2b) is C₁-C₆ alkyl.
 5. The compoundof any one of claims 1 to 4, wherein R³ is H.
 6. The compound of any oneof claims 1 to 5, wherein n is
 2. 7. The compound of any one of claims 1to 6, wherein R⁴ is H.
 8. The compound of any one of claims 1 to 7,wherein one of R⁵ and R⁶ is H and the other of R⁵ and R⁶ is C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₃ alkyl), trifluoromethyl substituted cyclopropyl, ortrifluoromethyl substituted cyclopropyl(C₁-C₃ alkyl).
 9. The compound ofany one of claims 1 to 8, wherein L¹ is


10. The compound of claim 9, wherein each of R^(12a) and R^(12b) is H;X^(a) is O; Z^(1a) is a bond or —(CH₂)₁₋₃—; and m1 is 0 or
 1. 11. Thecompound of any one of claims 1 to 8, wherein L¹ is


12. The compound of claim 11, wherein each of R^(12c) and R^(12d) is H;X^(a) is O; Z² is —CH₂—; Z^(1b) is a bond or —(CH₂)₁₋₃—; and m2 is 0or
 1. 13. The compound of any one of claims 1 to 8, wherein L¹ is*—Z^(1e)-Z³—(CH₂)_(m5)— and Z³ is —NR^(12g)—.
 14. The compound of claim13, wherein R^(12g) is H; Z^(1e) is a bond or —(CH₂)₁₋₃—; and m5 is 0or
 1. 15. The compound of any one of claims 1 to 8, wherein L¹ is


16. The compound of claim 15, wherein R^(12f) is H; Z^(1d) is a bond or—(CH₂)₁₋₃—; X^(a) is O; Ring A is phenyl; Y⁴ is —O— or —NH—; each of k4,p4 and m4 is independently 0 or
 1. 17. The compound of any one of claims1 to 8, wherein L¹ is

and Z³ is —NR^(12g)—.
 18. The compound of claim 17, wherein R^(12g) isH; Z^(1e) is a bond or —(CH₂)₁₋₃—; Ring A is phenyl; Y⁵ is —O— or —NH—;each of k5, p5 and m5 is independently 0 or
 1. 19. The compound of anyone of claims 1 to 8, wherein L¹ is


20. The compound of claim 19, wherein Z^(1f) is a bond or —(CH₂)₁₋₃—; m6is 0 or
 1. 21. The compound of any one of claims 1 to 20, wherein L² isa bond or —(CH₂)C(O)NH—.
 22. The compound of any one of claims 1 to 21,wherein X¹ is C₁-C₅ alkylene.
 23. The compound of any one of claims 1 to21, wherein X¹ is [—(CH₂)₂O-]₁₋₅, —[(CH₂)₂O]₁₋₅(CH₂)₂— or—(CH₂)₁₋₃—NR¹⁴—(CH₂)₁₋₃—, and wherein R¹⁴ is H or C₁-C₆ alkyl.
 24. Thecompound of any one of claims 1 to 23, wherein X² is —NHC(═O)—.
 25. Thecompound of any one of claims 1 to 24, wherein X³ is —S—.
 26. Thecompound of claim 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 27. A compound of Formula(II),

or a pharmaceutically acceptable salt thereof, wherein: R¹ is

wherein R¹ is optionally substituted with one or more R^(A); n is 1, 2or 3; each R^(2a) and R^(2b) is independently H, deuterium, halogen orC₁-C₆ alkyl; each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R^(A) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino,C₁-C₆ alkylamino, amino(C₁-C₆ alkyl), —(C═O)NR^(10a)R^(10b), (C₁-C₆alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionallysubstituted C₃-C₇ cycloalkyl; each of R⁴ and R⁶ is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,optionally substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl), or optionallysubstituted C₃-C₇ cycloalkyl; each of R^(5a), R^(5b) and R^(5c) isindependently H or C₁-C₆ alkyl; each of R^(7a) and R^(7b) isindependently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl; each of R^(8a) and R^(8b) is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,or C₃-C₈ carbocyclyl; each of R^(9a) and R^(9b) is independently H,optionally substituted C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₇-C₁₄ aralkyl, or optionally substituted C₃-C₈carbocyclyl; each R^(10a) and R^(10b) is independently H or C₁-C₆ alkyl,or R^(10a) and R^(10b) together with the nitrogen atom to which they areattached form an optionally substituted 5 or 6 membered heterocyclyloptionally substituted with one or more R¹¹; each R¹¹ is independentlyC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substitutedamino, halogen, or cyano; or two geminal R¹¹ form oxo; Q is CH₂ or C═O;L¹ is a bond

*—Z^(1e)-Z³—(CH₂)_(m5)—,

wherein the asterisk * indicates the point of connection to X¹; each ofZ^(1a), Z^(1b), Z^(1c), Z^(1d), Z^(1e), and Z^(1f) is independently abond or —(CR^(a)R^(b))_(q1)—; Z² is —(CR^(c)R^(d))_(q2)—; Z³ is a bond,O or NR^(12g); each of R^(a), R^(b), R^(c) and R^(d) is independently H,halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl; each q1 and q2is independently 1, 2 or 3; each X^(a) and X^(b) is independently O orS; each Ring A is independently phenyl or a five to six memberedheteroaryl, each optionally substituted with one or more R¹¹; each ofY¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is —NR^(12h)—, —O—, or —S— each R^(12a),R^(12b), R^(12c), R^(12d), R^(12e), R^(12f), R^(12g) and R^(12h) isindependently H or C₁-C₆ alkyl; each of m1, m2, m3, m4, m5, m6, k1, k2,k3, k4, k5, k6, p1, p2, p3, p4, p5, and p6 is independently 0, 1, 2, or3; L² is a bond, —(CH₂)₁₋₆NH—, —(CH₂)₀₋₆—C(═O)—, or —(CH₂)₀₋₃—C(═O)NR³—;R¹³ is H or C₁-C₆ alkyl; X¹ is C₁-C₁₅ alkylene or heteroalkylene; andRing B is phenyl or a 6 membered heteroaryl, optionally substituted withone or more R¹¹.
 28. The compound of claim 27, wherein the compound ofFormula (II) is also represented by Formula (II′):

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim27 or 28, wherein R¹ is


30. The compound of any one of claims 27 to 29, wherein R^(2a) is H. 31.The compound of any one of claims 27 to 30, wherein R^(2b) is C₁-C₆alkyl.
 32. The compound of any one of claims 27 to 31, wherein R³ is H.33. The compound of any one of claims 27 to 32, wherein n is
 2. 34. Thecompound of any one of claims 27 to 33, wherein R¹ is substituted withone R^(A) and wherein R^(A) is halogen or optionally substituted C₁-C₆alkyl.
 35. The compound of any one of claims 27 to 34, wherein each ofR^(5b) and R^(5c) is H.
 36. The compound of any one of claims 27 to 35,wherein L¹ is


37. The compound of claim 36, wherein each of R^(12a) and R^(12b) is H;X^(a) is O; Z^(1a) is a bond or —(CH₂)₁₋₃—; and m1 is 0 or
 1. 38. Thecompound of any one of claims 27 to 35, wherein L¹ is


39. The compound of claim 38, wherein each of R^(12c) and R^(12d) is H;X^(a) is O; Z² is —CH₂—; Z^(1b) is a bond or —(CH₂)₁₋₃—; and m2 is 0or
 1. 40. The compound of any one of claims 27 to 35, wherein L¹ is*—Z^(1e)-Z³—(CH₂)_(m5)— and Z³ is —NR^(12g).
 41. The compound of claim40, wherein R^(12g) is H; Z^(1e) is a bond or —(CH₂)₁₋₃—; and m5 is 0or
 1. 42. The compound of any one of claims 27 to 35, wherein L¹ is


43. The compound of claim 42, wherein R^(12f) is H; Z^(1d) is a bond or—(CH₂)₁₋₃—; X^(a) is O; Ring A is phenyl; Y⁴ is —O— or —NH—; each of k4,p4 and m4 is independently 0 or
 1. 44. The compound of any one of claims27 to 35, wherein L¹ is

and Z³ is —NR^(12g)—.
 45. The compound of claim 44, wherein R^(12g) isH; Z^(1e) is a bond or —(CH₂)₁₋₃—; Ring A is phenyl; Y⁵ is —O— or —NH—;each of k5, p5 and m5 is independently 0 or
 1. 46. The compound of anyone of claims 27 to 35, wherein L¹ is


47. The compound of claim 46, wherein each of R^(12c) and R^(12d) is H;X^(a) is O; Z^(1b) is a bond or —(CH₂)₁₋₃—; Z² is —(CH₂)₁₋₃—; Ring A isphenyl; and each of k2, p2 and m2 is independently 0 or
 1. 48. Thecompound of any one of claims 27 to 35, wherein L¹ is


49. The compound of claim 46, wherein Z^(1f) is a bond or —(CH₂)₁₋₃—; m6is 0 or
 1. 50. The compound of any one of claims 27 to 49, wherein X¹ isC₁-C₈ alkylene.
 51. The compound of any one of claims 27 to 49, whereinX¹ is [—(CH₂)₂O-]₁₋₅-, —[(CH₂)₂O]₁₋₅(CH₂)₂— or —(CH₂)₁₋₃—NR¹⁴—(CH₂)₁₋₃—and wherein R¹⁴ is H or C₁-C₆ alkyl.
 52. The compound of any one ofclaims 27 to 51, wherein L² is a bond, —C(O)—, or —(CH₂)C(O)NH—.
 53. Thecompound of any one of claims 27 to 52, wherein Ring B is phenyloptionally substituted with one or more R¹¹.
 54. The compound of any oneof claims 27 to 52, wherein Ring B is a 6 membered heteroaryl containingone, two or three nitrogen atoms, optionally substituted with one ormore R¹¹.
 55. The compound of claim 54, wherein Ring B is

each optionally substituted with one R¹¹.
 56. The compound of claim 55,wherein Ring B is


57. The compound of any one of claims 53 to 56, wherein R¹¹ is halogen.58. The compound of any one of claims 27 to 57, wherein R^(5a) ismethyl.
 59. The compound of any one of claims 27 to 58, one of R⁴ and R⁶is H and the other of R⁴ and R⁶ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₃alkyl), trifluoromethyl substituted cyclopropyl, or trifluoromethylsubstituted cyclopropyl (C₁-C₃ alkyl).
 60. The compound of any one ofclaims 27 to 59, wherein R⁴ is H and R⁶ is cyclopropyl(C₁-C₃ alkyl). 61.The compound of claim 27, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 62. A pharmaceuticalcomposition comprising a compound of any one of claims 1 to 61, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.
 63. A method ofdecreasing cellular levels of CDK, comprising contacting one or morecells with an effective amount of a compound of any one of claims 1 to61, or a pharmaceutically acceptable salt thereof.
 64. A method ofinhibiting the activity of CDK in a biological sample, comprisingcontacting the biological sample with an effective amount of a compoundof any one of claims 1 to 61, or a pharmaceutically acceptable saltthereof.
 65. The method of claim 63 or 64, wherein the cell is a cancercell selected from the group consisting of small cell lung cancer cell,non-small cell lung cancer cell, breast cancer cell, prostate cancercell, head and neck cancer cell, pancreatic cancer cell, colon cancercell, rectal cancer cell, teratoma cell, gastric cancer cell, ovariancancer cell, endometrial cancer cell, brain cancer cell, retinoblastomacell, leukemia cell, skin cancer cell, melanoma cell, squamous cellcarcinoma cell, liposarcoma cell, lymphoma cell, multiple myeloma cell,testicular cancer cell, liver cancer cell, esophageal cancer cell,kidney carcinoma cell, astrogliosis cell, relapsed/refractory multiplemyeloma cell, and neuroblastoma cell.
 66. A method of treating orameliorating a disease, disorder, or condition associated with CDK,comprising administering an effective amount of a compound of any one ofclaims 1 to 61, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition of claim 62, to a subject in need thereof;wherein the disease, disorder, or condition is small cell lung cancer,non-small cell lung cancer, breast cancer, prostate cancer, head andneck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma,gastric cancer, ovarian cancer, endometrial cancer, brain cancer,retinoblastoma, leukemia, skin cancer, melanoma, squamous cellcarcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer,liver cancer, esophageal cancer, kidney carcinoma, astrogliosis,relapsed/refractory multiple myeloma, or neuroblastoma.
 67. The methodof any one of claims 63 to 66, wherein the CDK is a wild-type, a mutantform of CDK, or is overexpressed.
 68. A method of treating orameliorating cancer, comprising administering an effective amount of acompound of any one of claims 1 to 61, or a pharmaceutically acceptablesalt thereof, or the pharmaceutical composition of claim 62 to a subjectin need thereof; wherein the cancer is small cell lung cancer, non-smallcell lung cancer, breast cancer, prostate cancer, head and neck cancer,pancreatic cancer, colon cancer, rectal cancer, teratoma, gastriccancer, ovarian cancer, endometrial cancer, brain cancer,retinoblastoma, leukemia, skin cancer, melanoma, squamous cellcarcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer,liver cancer, esophageal cancer, kidney carcinoma, astrogliosis,relapsed/refractory multiple myeloma, or neuroblastoma.
 69. The methodof claim 68, wherein the cancer is associated with CDK.